· web view?lithium - suggest levels?diabetic ketoacidosis/insulin physician consultation...

Case 7-09 Electrolytes

Patient ID 41-year-old female

Patient Location Medical Outpatients

Clinical Notes on Request FormPolyuria and polydipsia. Cause?

Case DetailsEarly morning spot urine

Osmolality 611 mmol/kg

Additional InformationOther laboratory results taken at the same time:Serum

Sodium 145 mmol/L (134–146)Potassium 4.3 mmol/L (3.4–5.0)Urea 8.5 mmol/L (3.0–8.0)Creatinine 84 µmol/L (45–90)Glucose 5.1 mmol/L (3.5–5.4)Ionised Calcium 1.23 mmol/L (1.12–1.32)Osmolality 302 mmol/kg (275–295)

Suggested CommentSuboptimal urine concentration in the setting of raised serum osmolality suggests possible partial diabetes insipidus. Suggest document degree of polyuria and consider fluid deprivation challenge with DDAVP administration to differentiate central from nephrogenic causes. Further endocrine review may be appropriate depending upon findings.

Rationale Timed urine collection helps document the degree of polyuria, and by definition should be >2.5–3 L/day. The present case shows raised serum osmolality, which makes primary polydipsia less likely. Urine is inadequately concentrated as one would expect a urine osmolality of >750 mmol/kg with this serum osmolality. This suggests (partial) diabetes insipidus, of either central or nephrogenic origin. The former is caused by inadequate antidiuretic hormone (ADH) production while the latter is due to inadequate ADH action on the renal tubules.

Formal fluid deprivation protocol (1) can help to resolve differential diagnosis with lack of further urine concentration following DDAVP in nephrogenic cases. Hypokalaemia, hyperglycaemia and renal impairment have been excluded as causes, although drugs, particularly lithium, may be contributory. Endocrine review with further pituitary studies may be appropriate depending on the findings.

Reference1. Baylis PH. Investigation of suspected hypothalamic diabetes insipidus. Clin Endocrinol (Oxf)

1995;43:507-10.

PREFERRED KEY WORDS LESS RELEVANT KEY WORDS

UNACCEPTABLE KEY WORDS

Consistent with dehydration Consider diabetes insipidusSuggest water deprivation test ± DDAVPInadequately concentrated urine?Nephrogenic diabetes insipidus?Central diabetes insipidusSuggest endocrinology consultation?Drug therapy?Lithium Rx

Serum osmolality raised?Diuretic useSuggest urine Na/electrolytesSlightly increased ureaSuggest 24 h urine collectionNormal serum Na/glu/Ca/KDiabetes mellitus excludedSuggest ADHNo osmolar gap?Renal disease?EthanolHigh normal sodiumNormal kidney functionNo evidence 1°/psychogenic polydipsiaNormal biochemical profileSuggest urine MC&SCreatinine upper end reference rangeSuggest eGFRConsider trial DDAVPRenal disease

Appropriate concentration of urine?Osmotic diuresisNo evidence of diabetes insipidusSuggest assess patient fluid statusSuggest repeat tests1°/psychogenic polydipsiaSuggest thyroid studies?Salt and water overloadAssess risk/investigate diabetes mellitusSuggest other testsElevated urine osmolalitySuggest CNS imaging/investigationSuggest urine urea?SIADHIncreased osmolar gapSuggest ACTH, cortisol?PregnantSuggest urine sodiumSerum osmolality normal?Hypoaldosteronism with salt wastingSuggest aldosterone:renin ratio?Fanconi syndrome?HyperthyroidismNo comment?HyperalimentationAvoid nicotine, alcohol, caffeineSuggest urine drug screen?Unmeasured soluteSIADH unlikelySuggest abdominal imagingNo polyuria by urine:serum osmolalityNormal urea, creatinine


Patient ID 51-year-old male

Patient Location Emergency Department

Clinical Notes on Request FormAcute confusional state. On risperidone.

Case DetailsPlasma

Sodium 108 mmol/L (136–146)Potassium 4.1 mmol/L (3.5–5.5)Creatinine 80 µmol/L (50–110)Urea 2.0 mmol/L (2.7–7.8)Osmolality 227 mmol/kg (280–300)

UrineSodium 12 mmol/LPotassium 8 mmol/LOsmolality 70 mmol/kg

Suggested CommentSevere hyponatraemia and a hypo-osmotic plasma with appropriately dilute urine and no evidence of salt wasting. This pattern is in keeping with primary (psychogenic) polydipsia with water intoxication. While risperidone is not necessarily the cause of the polydipsia, an alternative atypical antipsychotic may be more effective in improving psychogenic polydipsia.

Rationale Hyponatraemia is classified based on hydration status and plasma osmolality. The kidney’s response allows assessment of whether the cause is renal salt wasting. In this instance renal sodium loss is close to the <10 mmol/L usually applied to exclude renal salt loss and certainly below the >20 mmol/L used to rule-in salt wasting. The urine is appropriately almost maximally dilute, and is not suggestive of SIADH or dehydration (1). The results are most consistent with polydipsia, most commonly due to psychiatric illness and frequently affecting chronic schizophrenic patients.

While antipsychotics are a well-recognised cause of hyponatraemia (secondary to SIADH), the literature surrounding their effects on polydipsia is controversial. ‘Typical’ antipsychotics have been associated with aggravating polydipsia, while atypical antipsychotics have been reported to be useful in treating these patients (2). Risperidone has not been shown to be clearly effective in this group. At least one case in the literature cites risperidone as the likely cause (3).

References1. Burtis CA, Ashwood ER, Bruns DE (eds). Tietz Textbook of Clinical Chemistry and Molecular

Diagnostics. 4th Edition. St Louis: Elsevier Saunders; 2006. pp. 1751-53. 2. Bersani G, Pesaresi L, Orlandi V, et al. Atypical antipsychotics and polydipsia: a cause or a treatment?

Hum Psychopharmacol 2007;22:103-7.3. Kar N, Sharma PS, Tolar P, et al. Polydipsia and risperidone. Aust N Z J Psychiatry 2002;36:268-70.



Severe hyponatraemiaLow urine osmolalityLow urine sodiumConsistent with polydipsia?Psychogenic polydipsiaSuggests water intoxicationSecondary water intoxicationAcute water overload?Polydipsia?Due to risperidone Urine appropriately diluteNot suggestive of SIADHEvaluate total body waterDilutional hyponatraemiaSuggest withdrawal risperidone

Low plasma osmolalityHyponatraemia?Other drugsConfusion due to hyponatraemia?Extra-renal lossSuggest thyroid function testsDue to risperidoneLow plasma ureaAction requiredPatient history requiredCerebral oedema riskSuggest fluid restrictionSuggest glucoseMonitor resultsSuggest liver function testsCentral pontine myelinolysis risk with

rapid correctionRisk of deathCheck results repeatedPatient likely requires hypertonic salineRenal function tests normalCheck protein/lipidsRisk rhabdomyolysis during treatmentLow plasma sodium?Patient on fluid replacementSuggest drug screenContact Pathologist?Beer potomania

?SIADHSuggest water deprivation test?Adrenal insufficiency?HypothyroidismSuggest cortisol / synacthen stimulation test

?Cardiac/liver failure?Renal loss?HyperglycaemiaUrine not maximally diluteSuggest ADH?Alcoholism?Disease causing oedema?Diabetes insipidusCheck pituitary functionSuggest serum/urine myoglobin?Patient non-compliance?Increased sodium lossSodium depletion unlikelySuggest renal function tests ?Pseudohyponatraemia?Low salt intake?Renal failure?Reset osmostat


Patient ID 78-year-old man

Patient Location Nursing Home

Clinical Notes on Request FormDemented, percutaneous endoscopic gastrostomy (PEG) fed

Case DetailsSodium 169 mmol/L (135–145)Potassium 3.6 mmol/L (3.5–5.0)Chloride 121 mmol/L (98–107)Bicarbonate 37 mmol/L (21–32)Urea 18.0 mmol/L (2.0–8.5)Creatinine 90 µmol/L (60–110)

Suggested CommentProfound hypernatraemia with raised urea/creatinine ratio is suggestive of marked dehydration. Suggest urgent review of clinical volume status and fluid balance.

Rationale Marked hypernatraemia with elevated urea to creatinine ratio is consistent with dehydration, specifically water depletion. Percutaneous endoscopic gastrostomy (PEG) feeding tubes are increasingly used for patients who cannot maintain adequate nutrition with oral intake. They include patients with neurological disorders, other conditions where swallowing is impaired, or there is obstruction of the upper gastrointestinal tract.

Artificial feeding may cause metabolic problems, including deficiencies or excess of fluid, electrolytes, vitamins and trace elements. Hypernatraemia is usually due to inadequate water intake. Loss of water in excess of sodium may also be contributory. It may develop rapidly in patients who are unable to experience or communicate their thirst, and especially in institutionalised subjects, who are reliant on caregivers to maintain their fluid intake.

Reference1. Gault MH, Dixon ME, Doyle M, et al. Hypernatremia, azotemia, and dehydration due to high-protein

tube feeding. Ann Intern Med 1968;68:778-91.



Consistent with marked dehydrationMarked hypernatraemia?Inadequate water intake?Hypovolaemic hypernatraemiaIncreased urea/creatinine ratio?DehydrationWater/hypotonic fluid depletionCheck hydration statusReview feed compositionSuggest fluid replacement?Insufficient water in PEG feedSuggest IV fluid replacementUrgent treatment requiredCheck urine volume

Elevated ureaHypernatraemiaElevated bicarbonateSuggest urine/plasma osmolalityElevated chloride?Metabolic alkalosis?Diarrhoea/stomal loss?VomitingConsider urine sodium?Diabetes insipidusSuggest urine electrolytesSuggest glucose estimation?Increased salt intake?Diuresis?Pre-renal renal failureSuggest clinical reviewSuggest blood gas analysisConsistent with tube feeding syndromeLow normal potassium level?Skin/respiratory water loss?Secondary hyperaldosteronismExcessive salt intake is rare?HyperaldosteronismSuggest repeat urea and electrolytesHaemoconcentration?Head injury?Potassium depletionMonitor results during fluid treatment?Diuretic therapyExclude hypertonic fluid therapy?Gastrointestinal bleed?Loss of thirst reflectRisk coma/death?Meningitis/meningoencephalitis?Creatinine low due to muscle massSuggest urine creatinine?Malnourished?Saline-responsive metabolic alkalosisArtefact unlikelySuggest review fluid management?Mineralocorticoid Rx

?Drip arm?Renal failure?Catabolism?Cushing’s diseaseSuggest occult bloodNo commentSuggest cortisol/aldosterone?Compensated respiratory acidosisSuggest CK?Rhabdomyolysis



Patient Location General Practice

Clinical Notes on Request FormIncreased blood pressure

Case DetailsSodium 146 mmol/L (135–145)Potassium 3.6 mmol/L (3.5–5.0)Chloride 106 mmol/L (96–109)Bicarbonate 29 mmol/L (23–32)Urea 5.1 mmol/L (3.5–7.5)Creatinine 100 µmol/L (40–120)Cholesterol 5.8 mmol/L (3.9–5.5)Triglyceride 1.4 mmol/L (0.6–2.0)

Suggested CommentIn the setting of borderline hypokalaemia and high-normal bicarbonate, consider possible secondary causes of hypertension. Measurement of renin and aldosterone might be helpful and further investigations of mineralocorticoid excess, if clinically indicated. Suggest repeat full fasting lipid profile and evaluate in context of absolute cardiovascular risk status.

Rationale Borderline hypokalaemia and high-normal bicarbonate in the setting of hypertension should prompt review for secondary causes such as diuretic therapy. Renin and aldosterone would be appropriate to investigate possible mineralocorticoid excess. This should be considered in patients with blood pressures of >160 mmHg (systolic and >100 mmHg (diastolic), drug-resistant hypertension, hypertension with: spontaneous hypokalaemia or diuretic-induced hypokalaemia, adrenal incidentaloma, family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years), and patients with first degree relatives diagnosed with primary aldosteronism.

Investigations for Cushing’s syndrome would depend on clinical index of suspicion. Full fasting lipid profile should be repeated and any intervention determined by the absolute cardiovascular risk status, which depends on full clinical evaluation and cannot be assigned on the basis of the results alone. It is not appropriate to comment on any possible drug intervention.

Reference1. Chao CT, Wu VC, Kuo CC, et al. Diagnosis and management of primary aldosteronism: an updated

review. Ann Med 2013;45:375-83.



Mild hypernatraemiaHigh normal bicarbonateLow normal potassium?1°/2° hyperaldosteronismSuggest renin/aldosterone?Cushing’s syndromeSuggest mid-stream urine test Suggest further investigationsAssess cardiovascular disease risk factorsCholesterol and triglyceride insufficient

to assess cardiovascular disease riskAssess 2° causes hyperlipidaemiaReview lifestyle associated risk factorsSuggest fasting glucoseMildly elevated cholesterolSuggest fasting lipid profileSuggest HDL/LDL?Drugs?Diuretic therapy

Hypertension notedIncreased risk cardiovascular diseaseAssess 2° causes hypertension?Diabetes mellitusSuggest TSHSuggest repeat testingSuggest cortisol/ACTHConsider drug therapy if clinically

indicatedExclude liquorice ingestioneGFR=67 mL/min/1.73m2

?PhaeochromocytomaSuggest liver function testsSuggest repeat urea and electrolytesTriglycerides within normal rangeHypertension probably idiopathicPatient most likely fastingRelative hypochloraemiaNormal bicarbonateNormal ureaModerately elevated cholesterolSuggest 24 hour urine cortisolSuggest baseline liver function testsSuggest fT4?Renal artery stenosisReview history of familial

hypercholesterolaemiaProceed to glucose tolerance test if

glucose ≥6.1 mmol/LMild renal disease not excludedSuggest calciumeGFR=72 mL/min/1.73m2

?Stage II chronic kidney diseaseHypokalaemic metabolic alkalosis?DehydrationSuggest plasma metanephrines

Suggest microalbuminSuggest urateSuggest angiotensinSuggest urine and serum osmolalityNational Heart Foundation target for high risk total cholesterol <4.0 mmol/L

Chronic renal failure excludedSuggest ECGTreat cardiovascular risk factors

aggressively No commentNormal electrolytes, urea, creatinine


Patient ID 32-year-old woman


Clinical Notes on Request FormMarked weakness – poor diet, but no anorexia; denies laxatives and diuretics use.

Case DetailsSodium 139 mmol/L (134–146)Potassium 1.4 mmol/L (3.4–5.0)Chloride 110 mmol/L (98–108)Bicarbonate 15 mmol/L (22–32)Urea 6.5 mmol/L (3.0–8.0)Creatinine 118 µmol/L (45–90)eGFR 49 mL/min/1.73m2 (>60)Calcium 2.44 mmol/L (2.15–2.60)Magnesium 1.26 mmol/L (0.70–1.10)Phosphate 0.42 mmol/L (0.80–1.40)Total protein 83 g/L (60–80)Albumin 41 g/L (35–50)Bilirubin 10 μmol/L (<20)ALT 92 U/L (<35)GGT 84 U/L (<40)ALP 104 U/L (35–135)TSH 20.6 pmol/L (0.4–4.0)fT4 9.0 mU/L (9.0–19.0)

Additional InformationHb 157 g/L (115–160)WCC 23.5 x109/L (4.0–11.0)Platelet 528 x109/L (150–400)Hct 0.44 (0.37–0.47)MCV 91 fL (80–100)MCH 32 pg (27–32)

Suggested CommentSevere hypokalaemia and hypophosphataemia with a normal anion-gap metabolic acidosis and renal impairment. The differential includes renal tubular acidosis (RTA, distal or proximal), and acute diarrhoea or laxative abuse. Hypothyroidism, leucocytosis and thrombocytosis and raised ALT noted. Suggest blood gases, urine pH, urine ammonia, and electrolytes. Possible muscle source for ALT - suggest measurement of CK to confirm.

Rationale This complex case involves a 32-year-old woman with profound hypokalaemia and a normal anion gap metabolic acidosis. Additionally she has moderate hypophosphataemia, hypermagnesaemia, renal impairment, hypothyroidism, a leucocytosis/thrombocytosis and a raised ALT. The comment should focus on the major abnormality (severe hypokalaemia) and should discuss the differential diagnoses of hypokalaemic acidosis rather than the much broader differential of hypokalaemia. Renal tubular acidosis (RTA, distal or proximal), acute diarrhoea, and dialysis treatment are all possibilities. Carbonic anhydrase inhibitors or transplantation of the ureters into the colon should be excluded also.

Further investigations should include blood gases, urine pH (>5.5 in distal RTA; <5.5 in proximal RTA), urine ammonia (<33 μmol/min in distal RTA; >33 μmol/min in proximal RTA), electrolytes, and a laxative screen if suspicion remains. The urine pH and ammonia should be measured when patient is in acidosis. Muscle is the possible cause of the raised ALT; a CK measurement would be useful to confirm this. Recommend repeat thyroid function tests after resolution of the acute episode would be useful.



Marked hypokalaemiaModerate hypophosphataemiaAcidosisNormal anion gap metabolic acidosisHypokalaemic metabolic acidosisRenal tubular acidosis?Renal potassium loss?GI loss ?diarrhoea ?vomiting?Laxative abuseMeds review ?Carbonic anhydrase

inhibitorsSuggest blood gas analysisSuggest urine/plasma pHSuggest urine K, pH, PO4, Mg, Ca, anion

gap?Drug use/screenHypothyroidismRepeat thyroid function tests after illness

settledPotassium replacement requiredHypokalaemia with associated myopathySuggest serum CK/AST?Ureteral diversion and/or obstruct ?Fanconi’s syndromeSuggest urine amino acids

Renal impairmentSuggest glucose/insulin/glucose tolerance

test/urine glucoseHepatocellular injury?Autoimmune disease ?Hashimoto’sSuggest thyroid antibodiesHyperchloraemia?Sepsis, suggest further investigation?Diuretic use/abuseLeucocytosis and thrombocytosisHypermagnesaemia?Malnutrition?Antacids use/abuse - high magnesiumExclude urinary tract infection/

microscopy, culture and sensitivity?Lithium - suggest levels?Diabetic ketoacidosis/insulinPhysician consultation required - urgentSuggest urine protein?Hypokalaemic periodic paralysisHypothyroid hypokalaemic periodic

paralysisSick euthyroid syndromeSuggest urine uric acid/PO4/NH4Faecal electrolytes/Mg confirm high MgPossible refeeding syndromeInfection/allergy/inflammation - suggest

CRPNH4Cl loading test for renal tubular

acidosisRepeat renal function testsPotassium redistribution to cells -

insulin/B-agonistsPhosphate supplement requiredHypokalaemiaToluene abuseExclude artefactual potassium reductionExclude transient cause of low potassium?Respiratory alkalosisExclude hypertensionSuggest 24 h urine cortisol/creatinine/K?Past treatment for hyperthyroidism?Respiratory alkalosis?Carcinoma ?villous tumourNo evidence of poor dietSuggest urine proteinMarked hypophosphataemia

?Ethanol- induced liver dysfunctionSuggest cortisol/ACTH?Malignancy?Wilson’s disease, investigate further?Adrenal insufficiencySuggest cortisol/synacthen test?Cushing’s syndrome?Secondary hyperthyroidism?Steroids?Possible hyperparathyroidMarked hyponatraemia?Pituitary adenoma with 2° hypothyroidism

?Excessive liquorice ingestionSuggest HIV screenSuggest TRH test for differential diagnosis

Suggest B12/folate and iron?Liddle’s/Bartter’s syndromeNormal magnesium levelSuggest TSH with different method ?

heterophile antibodiesSuggest serum/urine electrophoresisSuggest autoimmune screen - ANA/ENASuggest renin/aldosterone?HyperaldosteronismSuggest serum electrolytes, Mg, CaSuggest urine/plasma osmolality?Light chains




Clinical Notes on Request FormPolyuria.

Case DetailsSodium 146 mmol/L (136–145)Potassium 3.9 mmol/L (3.5–5.1)Chloride 104 mmol/L (98–107)Bicarbonate 31 mmol/L (22–29)Urea 4.8 mmol/L (3.5–7.2)Creatinine 86 µmol/L (44–80)eGFR 55 mL/min/1.73m2 (>90)Serum Osmolality 299 mOsm/kg (280–300)Urine Osmolality 166 mOsm/kg (40–1400)

Suggested CommentThe inappropriately dilute urine for the given serum osmolality may indicate diabetes insipidus (DI). Recommend serum calcium measurement and a review of medications for possible causes, and consider referral for endocrinology review.

Rationale Diabetes insipidus (DI), the inability to concentrate urine, is an important differential diagnosis in the investigation of polyuria. A high urine volume coupled with low urine osmolality measured in the setting of a supervised or overnight water deprivation test is pathognomonic. A low osmolality (<200 mOsm/kg) in a random urine sample is unhelpful unless the serum osmolality at the same time is >295 mOsm/kg, indicating relative dehydration. By contrast a high urine osmolality >700 mOsm/kg in a random urine sample can be useful to exclude DI, often suggesting urinary frequency rather than true polyuria.

Psychogenic polydipsia, the main differential diagnosis for polyuria typically presents with low or low-normal plasma osmolality, as the primary problem here is excessive water intake. Causes of DI may be central (antidiuretic hormone (ADH) deficiency) e.g. head trauma, pituitary disease, or nephrogenic (ADH resistance) e.g. hypercalcaemia, lithium therapy. Response to exogenous ADH distinguishes these two major forms.

References1. Bichet DG. Diagnosis of polyuria and diabetes insipidus. In: UpToDate, Sterns RH and Emmett M

(Eds), UpToDate, Waltham, MA; 2013.2. Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a complex disease. Cleve

Clin J Med 2006;73:65-71.


NOT SUPPORTED KEY WORDS

High normal serum osmolalityLow urine osmolalityInappropriate dilute urineInappropriate diuresisUrine osmolality consistent with water

diuresisExcessive water loss?Diabetes insipidus (DI)Suggest serum/plasma calciumReview drugs/medicationsHistory of polyuria noted?Lithium therapy?Cranial/central or nephrogenic DI?Medication relatedSuggest (endocrine) referralDehydration?HypercalcaemiaDiscuss fluid intake with patient

Suggest water deprivation testBorderline hypernatraemia24 h urine volume to confirm polyuriaDecreased eGFR?Diuretic therapy relatedSuggest urinalysisDesmopressin to differentiate

cranial/nephrogenic DISuggest ADHMildly elevated creatinineMildly elevated bicarbonateMild (metabolic) alkalosisUrine osmolality < serum osmolality?Osmotic diuresis?Renal ADH resistancePhone GP?Metabolic?Iatrogenic?Urinary tract infectionReview family historySuggest referral to nephrologist

?Primary polydipsiaCreatinine consistent with stage 3 renal disease

?Chronic kidney disease (CKD)/ renal disease

Suggest imaging?Cushing’s/Conn’sRepeat early morning urine osmolalitySuggest aldosterone/renin ratio?Diabetes mellitusSuggest serum electrophoresis?Thyrotoxicosis/suggest thyroid function tests

Normal osmolar gapSuggest serum cortisol?Liquorice useSuggest 24 h urine cortisolSuggest comprehensive biochem profileSuggest full blood countSuggest hospital referral?High water intakeSuggest HbA1CPrimary water deficitSuggest ACTHSuggest microalbuminStage II CKD

MISLEADING KEY WORDS

?Age relatedSuggest repeat in 3–6 monthsInappropriate ADH secretionSuggest renal biopsy

Case 12-04 Acid-Base



Clinical Notes on Request FormRenal failure. Dizzy.

Case DetailsBlood GasesSample type: venous

pH 7.22 (7.35–7.45)pCO2 54 mmHg (35–45)pO2 75 mmHg (80–110)HCO3 22 mmol/L (22–30)Base Excess -6 mmol/L (-3/+3)O2 Sat. 92 %Na 121 mmol/L (135–148)K 7.3 mmol/L (3.5–5.3)iCa 1.05 mmol/L (1.13–1.32)Note: all reference intervals shown are for arterial blood only.

Suggested CommentCritical electrolyte and calcium results, while consistent with renal failure, require confirmation by repeat sample before initiating treatment. Serum creatinine and urea should also be measured urgently. Provided the patient is not in circulatory shock, the pH reliably indicates an acidaemia; most likely metabolic but also with a respiratory component given the high pCO2. Assessment of oxygenation is unreliable and if required, should be assessed by pulse oximetry and arterial blood gas analysis.

Rationale There is growing evidence that, in certain situations, venous blood gas analysis provides adequate and reliable information to allow one to avoid the more painful and potentially dangerous practice of arterial blood sampling. Venous sampling is particularly useful in diabetic ketoacidosis and uraemic patients. There is currently insufficient evidence to support its use in compromised circulatory states (e.g. arrest/ shock) and mixed acid-base disorders as the relationship between arterial and venous blood gas parameters may change in these situations.

pH and bicarbonate results are virtually interchangeable with arterial values, thus allowing for acid-base assessment. pCO2 values are generally 6 mmHg higher in venous blood. At the diagnostic cut-off of 45 mmHg (i.e. the arterial blood cut-off), venous pCO2 has high sensitivity (nearly 100%) but poor specificity (56%) as a screening test for arterial hypercarbia. pO2 values are less than half of those in arterial blood and consequently no comment regarding hypoxia should be made from venous samples. Hyperkalaemia due to haemolysis is always possible but less of a concern here given the pattern of abnormalities and the clinical context. Communication should focus clinical staff on immediate confirmation of these abnormal results before urgent medical treatment.

References1. Kelly AM. Review article: can venous blood gas analysis replace arterial in emergency medical care.

Emerg Med Australas 2010;22:493-8.2. Verma AK, Roach P. The interpretation of arterial blood gases. Aust Prescr 2010;33:124-9.



Venous blood gas sampleCritical hyperkalaemia and

hyponatraemiaSevere hyperkalaemiaSevere hyponatraemiaAcidaemia?Low Ca 2° to renal failureConsistent with mixed respiratory and

metabolic acidosisConsistent with renal failureNa, K, Ca consistent with renal failure Suggest repeat electrolytes/CaSuggest renal function tests?Respiratory disease/pneumonia/

pulmonary oedemaVenous pO2 not reliableUrgent medical attention required

Recollect arterial blood sampleMetabolic acidosisSuggest glucose?High potassium due to haemolysis, excess cold

?Drugs/medications?Diabetic ketoacidosisSuggest test for adrenocortical

insufficiency?Respiratory failureRespiratory acidosisReference intervals are for arterial bloodLow pH and high pCO2Suggest urine K, Na, protein?Diuretics/spironolactoneSuggest anion gapSuggest serum and urine osmolality?O2 therapyBicarbonate loss?Adrenal insufficiencySuggest CXRHypercarbia?Spurious hyperkalaemiaHyperkalaemia caused by acidosisAcidosisAcute respiratory acidosisHigh K, low CaMild hypocalcaemiaSuggest cardiac monitoring?Clinical symptoms due to low Na?Lactic acidosisNo respiratory compensationSuggest nephrology reviewHyponatraemia due to renal failureSevere acidosisNo comment?Dizziness due to hypocalcaemiaMixed acid base disorder

Consistent with arterial sampleSuggest dialysisRespiratory compensationSuggest PTH/Ca/Mg/Vitamin D/ALP?Specimen contaminationSuggest urine pH?Renal tubular acidosisDifficult to assess respiratory componentLack of renal compositionLow Ca due to critical illnessVenous blood gas difficult to commentSuggest renal ultrasoundSIADH?Chronic respiratory acidosisAcute on chronic respiratory acidosisMetabolic compensationMixed metabolic acidosis and respiratory

alkalosisSuggest Cl for RTA

MISLEADING KEY WORDS?Cerebral diseaseO2 status acceptable for elderlyHypoxia and cyanosis

Case 13-06 Acid-Base



Clinical Notes on Request FormNo information provided

Case DetailsSodium 150 mmol/L (137–145)Potassium 3.0 mmol/L (3.5–4.9)Chloride 127 mmol/L (100–109)Bicarbonate 13 mmol/L (22–32)Urea 24.9 mmol/L (2.7–8.0)Creatinine 102 µmol/L (50–100)

Previous renal surgery

Venous blood gas analysispH 7.22 (7.34–7.45)pO2 31 mmHg (25–40)pCO2 29 mmHg (40–50)Calc. Bicarb 12 mmol/L (22–31)

Suggested CommentSignificant metabolic acidosis with hypokalaemia and normal anion gap. Hypernatraemia suggests dehydration. Possible causes include: renal tubular acidosis, severe diarrhoea, or ureteric diversion. If the cause is unknown, suggest check urinary pH and electrolytes. If considering parenteral bicarbonate, it is important to normalise potassium beforehand.

Rationale Normal anion gap metabolic acidosis can occur due to bicarbonate loss (e.g. severe diarrhoea, ureteric diversion to the colon, or proximal renal tubular acidosis, also known as type II RTA); failure of acidification in the distal renal tubule (type I RTA); or excess ammonium retention (e.g. ureteric diversion to the colon). If the ureter is diverted to the ileum, acidosis is unlikely unless there is obstruction and prolonged urine-gut contact. Loss of bicarbonate and fluid volume leads to compensatory retention of sodium and chloride, and hyperchloraemia.

Urine pH should be <5.3 in acidosis, if renal acidification is normal. However, severe volume depletion may increase urine pH. High urine pH can be followed up by loading tests with bicarbonate or ammonium if necessary to localise the site of RTA. Increasing blood pH shifts potassium into cells so it is important to correct the hypokalaemia, then monitor potassium closely during treatment of any acidosis.

References1. Walmsley RN, White GH. Normal “anion gap” (hyperchloremic) acidosis. Clin Chem 1985;31:309-13.2. Cruz DN, Huot SJ. Metabolic consequences of urinary diversions: an overview. Am J Med

1997;102:477-84.3. Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160-70.



Normal anion gap metabolic acidosisHypernatraemia/dehydration/increased

urea:creatinine?Renal tubular acidosisType II (proximal) renal tubular acidosisType I (distal) renal tubular acidosisMetabolic acidosis?Diarrhoea/gastrointestinal lossSuggest urinary electrolytesSuggest urine pH?Urinary diversion?Obstructed ileal bladder?Vesicocolic fistula

HypokalaemiaHistory of renal surgery(Partial) respiratory compensation?(Acute) renal impairment?Carbonic anhydrase inhibitorsSuggest serum/urine osmolalitySuggest glucose/insulinLow bicarbonateSuggest albumin/total

protein/phosphate/Ca/MgSuggest urine ammonia?Renal or gastrointestinal diseaseFurther clinical info neededLoss of bicarbonateLow pH/ acidaemiaLow pCO2Venous blood gas sample notedSuggest specialist referralPhone result?Dietary intake?Chronic laxative abuse?Villous adenomaSuggest lactate/citrateSuggest repeat testingDiuretic phase following acute tubular

necrosisSuggest troponin/cardiac markers/ECG?NephrolithiasisSuggest ammonia chloride loading?Increased osmotic diuresis

?(Resolved) diabetic ketoacidosisSuggest serum electrolytes, urea, creatinine

Uncompensated metabolic acidosis?Vomiting/ infectionTreat with IV potassium and insulin?Salt ingestion/water depletionIngestion of ammonium chloride ?Drug reaction


?Saline/IV contamination?Diuretics?Mineralocorticoid excessFluid status unknown?Cholestyramine

Case 6-06 Renal



Clinical Notes on Request FormNewly diagnosed with type II diabetes mellitus.?Microalbuminuria

Case DetailsSample: morning spot urine

Albumin 12 mg/LCreatinine 3.9 mmol/LACR 3.1 mg/mmol (<3.5)

Additional InformationNo previous urine results.

Suggested CommentNormal results. Suggest repeat in one year.

Rationale Patients with type II diabetes mellitus should be tested for albuminuria annually starting from the time of diagnosis. The albumin:creatinine ratio (ACR) is the preferred method for assessment of albuminuria in both diabetic and non-diabetic individuals. The ACR should be measured using a first morning spot urine specimen; however, a random urine sample is also acceptable when the former is not possible or practical. Alternately, the albumin excretion rate (AER) may be measured using 24 h urine collection.

Microalbuminuria is indicated by ACR 2.5–25 mg/mmol in malesACR 3.5–35 mg/mmol in females

OR AER 30–300 mg/24 h in either gender

Macroalbuminuria is indicated by:ACR >25 mg/mmol in malesACR >35 mg/mmol in females

ORAER >300 mg/24 h in either gender

If the ACR or AER is positive for microalbuminuria, the person should have one to two additional ACR/AER within three months. Microalbuminuria is confirmed if two of three tests are positive. If the ACR or AER showed macroalbuminuria, total protein should be measured in a 24 h urine collection. If the ACR is normal, as it is in this patient, testing should be repeated annually.

Reference1. Johnson DW, Jones GR, Mathew TH, et al.; Australasian Proteinuria Consensus Working Group.

Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Med J Aust 2012;197:224-5.



Normal resultRecheck 6–12 monthsFurther monitoring suggested

Results exclude microalbuminuriaSuggest AERCriteria 2/3 in 6 weeks =

microalbuminuriaRepeat ACRSuggest HbA1cNo commentACR borderlineMorning urine preferredSuggest plasma creatinineMonitor cardiovascular risk factorsSuggest three timed overnight urinesMicroalbuminuria may develop laterAlbumin fragments may not be detectedSuggest creatinine clearanceSuggest lipids

No nephropathyUrine creatinine low, ?dilutedMicroalbuminuria presentExclude urinary tract infection, exercise, cystic fibrosis

AER >20 x2 = microalbuminuriaAER <20 not microalbuminuriaADS recommends 12 month monitorUrine albumin and creatinine slightly high

Incomplete and inappropriate sampleCheck urine glucose levelACR unreliable, dilute urine

Case 6-10 Renal


Patient Location Medical Ward

Clinical Notes on Request FormParoxysmal nocturnal haemoglobinuria

Case DetailsSodium 136 mmol/L (134–146)Potassium 4.0 mmol/L (3.4–5.0)Bicarbonate 21 mmol/L (22–32)Urea 26.7 mmol/L (3.0–8.0)Creatinine 552 µmol/L (60–120)

Additional InformationTotal Protein 63 g/L (60–80)Albumin 34 g/L (35–50)Bilirubin 55 µmol/L (<20)Haemoglobin 94 g/L (135–180)Reticulocytes 4.1% (0.2–2.0)Blood film features suggest active haemolysis.Haem Index 470 (<100)

Suggested CommentThis patient has renal failure. Elevated serum haemoglobin indicates haemolysis. Clinical note of paroxysmal nocturnal haemoglobinuria suggests in vivo haemolysis, in which case the measured potassium reflects circulating concentration. Repeat measurement of potassium is recommended for confirmation.

Rationale Paroxysmal nocturnal haemoglobinuria is a condition characterised by the clonal expansion of one (usually the red blood cell line) or more haemopoietic stem cells that are deficient in certain surface proteins. These are acquired through somatic mutations, which predispose the blood cells to complement-mediated haemolysis, particularly in acidic conditions. This may lead to haemoglobinuria/haemosiderinuria that can damage the kidneys. Traditionally, the haemolysis is thought to occur in paroxysms during sleep-induced acidosis. More recent evidence suggests it can occur throughout the day but the haematuria is more notable in the concentrated overnight urine.

The clinical note given with the biochemistry results should assist with the interpretation of those specific results. The patient is clearly in renal failure. The evidence for intravascular haemolysis is the raised serum haemoglobin as measured by the haem index, bilirubin and reticulocytes, and blood film features.

Other supportive features of this intravascular haemolytic condition include elevated serum lactate dehydrogenase, low/absent haptoglobin, haemoglobinuria/haemosiderinuria. Complications of paroxysmal nocturnal haemoglobinuria include iron deficiency anaemia, hyoplastic bone marrow and thrombosis, which may involve the liver, brain, abdominal and lower limb venous systems, and can be fatal.

Reference1. Krauss JS. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Ann Clin Lab Sci

2003;33:401-6.



Renal failureIntravascular haemolysisConsistent with paroxysmal nocturnal

haemoglobinuriaSuggest haptoglobinSample haemolysedIn vivo potassium okay?In vitro or in vivo haemolysisBilirubin affected by haemolysisRepeat potassium on nonhaemolysed

sample

Expected higher potassiumSuggest cell markers by flow cytometryHyperbilirubinaemiaHaemolytic anaemia?Renal haemosiderosisActive red blood cell production/

increased reticulocytesAnaemia/low haemoglobin?Renal failure due to haemoglobinuriaSuggest LDHElevated urea and creatinineSuggest complete haematologyAnaemia multifactorialRenal failure 2° to paroxysmal nocturnal

haemoglobinuriaSuggest liver function tests and

direct/indirect bilirubinSuggest iron studies/erythrocyte folateSuggest direct Coombs’ Test?Other concurrent diseaseSuggest haematology consultation?Thrombotic thrombocytopaenic purpura

and haemolytic uraemic syndromeSuggest urine protein/castsConsult with renal physicianSuggest monitor renal failure?Creatinine underestimated?Clinical information?Disseminated intravascular coagulationHaemolytic jaundice?Clinical dehydrationSuggest renal biopsy?Paroxysmal cold haemoglobinuria

Suggest urine haemoglobin and haemosiderin

Suggest Ham test?Renal failure 2° to thrombosisNo commentMonitor serum potassium?Previous renal function history?Non-paroxysmal nocturnal haemoglobinuria cause of renal failure

Recommend dialysis/exchange transfusion

?Blood transfusion?Soluble transferrin receptor assay?Erythrocytes protoporphyrin high?Sepsis or thrombotic thrombocytopaenic purpura

Suggest MRI/CT scansSuggest neutrophil ALP scoreCategorise paroxysmal nocturnal haemoglobinuria by CLST

Suggest cardiac markersSuggest Donath-Landsteiner testLiver function okaySuggest B-haem streptococcus cultureSuggest fine needle aspirationRenal recovery as potassium normalTransfusions and iron therapiesManage complications of paroxysmal nocturnal haemoglobinuria

Low albumin due to proteinuriaSuggest eGFR

Case 7-04 Renal



Clinical Notes on Request FormRoutine health check. Fit and well.

Case DetailsUrea 6.1 mmol/L (2.7–7.8)Creatinine 120 µmol/L (50–110)eGFR 45 mL/min/1.73m2 (80–120)Glucose (random) 4.7 mmol/L (3.5–7.8)Bilirubin 6 μmol/L (3–21)ALP 54 U/L (30–120)GGT 17 U/L (10–35)ALT 50 U/L (0–30)

Additional InformationNo previous laboratory results.

Suggested CommentMildly elevated creatinine and decreased eGFR suggests possible renal impairment, along with a minor increase in ALT. eGFR is not reliable in the presence of extreme lean body mass, high protein, vegetarian diets or creatine supplements. Consider urine protein, mid-stream urine sample and formal creatinine clearance if there is suspicion that eGFR may be incorrect and review patient for causes of increased ALT.

Rationale The estimated Glomerular Filtration Rate (eGFR) is derived from serum creatinine, age and sex using the CKD-EPI equation and it should be automatically reported with every creatinine requested in subjects >18 years of age (1). eGFR results may be unreliable or misleading in subjects with the following: acute changes in kidney function, on dialysis, exceptional dietary intake (e.g. vegetarian diet, high protein diet, creatine supplements), extremes of body size, skeletal muscle diseases, and severe liver disease.

An elevated ALT in an asymptomatic subject may be due to alcohol-related liver injury, chronic hepatitis B or C, autoimmune hepatitis, fatty liver disease, haemochromatosis, Wilson’s disease, or alpha-1-antitrypsin deficiency (2). Non-hepatic causes include coeliac sprue, muscle diseases, and strenuous exercise.

References1. Kidney Health Australia. http://www.kidney.org.au 2. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J

Med 2000;342:1266-71.

http://www.kidney.org.au/



Check urine albumin/proteinIncreased creatinineReduced eGFRIncreased ALTRenal impairment/diseaseRepeat creatinine/eGFR?Medication/drugsSuggest viral/hepatitis serologySuggest creatinine clearance?HepatitisSuggest mid-stream urine sample?Increased muscle masseGFR not valid in some situationsExtreme body composition eGFR not

validated?DietSuggest clinical review

Moderate chronic kidney diseaseAssess cardiovascular risk factorsMild liver diseaseRenal referral recommendedRepeat liver function testsMonitor resultsFollow-up requiredSuggest full liver function testsC-reactive protein / lipids?Fatty liver?AlcoholRefer to Kidney Foundation website?Creatinine method interferenceFull blood countNormal ureaSuggest Cockcroft-Gault/body surface

area calculationCheck glomerular haematuriaReview renal risk factors

?ImmunologicalMeasure blood pressureCheck for diabetesPTH/calcium studiesMeasure calcium/phosphateFasting glucoseNo dehydrationHS/iron studies?Acute renal failureNo commentConsider starting renal therapyConsider liver imaging Suggest other miscellaneous tests

Case 10-01 Renal



Clinical Notes on Request Form?Renal impairment. Blood pressure normal

Case DetailsSodium 139 mmol/L (134–146)Potassium 4.6 mmol/L (3.4–5.0)Glucose 5.1 mmol/L (3.0–5.4)Bicarbonate 28 mmol/L (22–32)Urea 8.2 mmol/L (3.0–8.0)Serum creatinine 133 μmol/L (60–110)eGFR 49 mL/min/1.73m2 (>60)

Additional InformationPrevious serum creatinine 129 μmol/L 6 months ago

Suggested CommenteGFR between 30 and 60 mL/min/1.73m2 on two occasions 6 months apart indicates stage 3 chronic kidney disease (CKD). Minimal change in serum creatinine indicates stable kidney function. Suggest assess coronary vascular disease (CVD) risk and check for albuminuria (urine albumin:creatinine ratio, ACR) and haematuria (dipstick). If ACR/dipstick is normal, re-assess in 12 months. If albuminuria and/or haematuria present, repeat ACR/dipstick tests (considered present if two of three repeat tests are positive for ≥3 months) and consider further investigation including renal U/S and referral to a nephrologist.

Rationale and ReferenceseGFR should be estimated by applying CKD-EPI equation on isotope dilution mass spectrometry-traceable creatinine assays. Age-related decision points for eGFR in adults are not recommended, as an eGFR < 60 mL/min/1.73 m2 carries significantly increased risks of adverse clinical outcomes without consistent age association. Hence, whilst it is very common in older people, it should not be considered a normal part of ageing.

Initial further investigations suggested include (preferably first morning void) urine albumin:creatinine ratio (ACR) and dipstick (for haematuria), monitoring of serum creatinine and cardiovascular risk assessment. If no abnormalities are found, a wait-and-watch approach is appropriate with yearly reviews. Note the reduced GFR should be taken into account when making drug-dosing decisions, and attention paid to cardiovascular risk reduction. However, if the investigations show abnormalities, the need for further investigations and specialist referral should be considered.

References1. Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and automatic reporting of

estimated glomerular filtration rate: new developments and revised recommendations. Med J Aust 2012;197:224-5.

2. Kidney Health Australia – Health Professionals section. http://www.kidney.org.au

http://www.kidney.org.au/

PREFERRED KEY WORDS

LESS RELEVANT KEY WORDS


eGFR suggests moderate CKD (stage 3)Consistent with renal impairmentStable creatinine resulteGFR declines with ageInterpret eGFR with caution in elderlyTypical for age if stable and no other

abnormalitiesIf stable, no other abnormalities,

unlikely CKDAssess CVD risk factorsSuggest ACRSuggest test for proteinuriaSuggest test for haematuriaSuggest fasting lipid profileMonitor eGFR 3–6 monthlyBeware renal excretion for drugs with

low GFRInvestigate furtherRefer to nephrologist if indicated

Slightly raised creatinine and ureaLow eGFRMild renal impairment?Lifestyle habits/underlying causes?Normal GFR for ageSuggest spot protein/creatinine ratioSuggest 24 h urine protein excretionSuggest Ca/PO4/PTH/vit D?Renal impairmentApply eGFR as recommendedNo comment?Muscle mass and dietary intakeDue to postrenal or ?intrarenal causeClinical correlations requiredSuggest cystatin CSuggest mid-stream urine examinationseGFR by MDRD uses creatinine, sex and

age?Drugs that interfere with eGFRConsider patient age and creatinine

uncertainty of measurementElectrolytes normalReview patient (Kidney Health Plan)?Hydration statuseGFR 10th percentile for age & sexUse surface area corrected eGFReGFR use in stable medical conditionseGFR inappropriate for drug dosingSuggest iron studiesSuggest imaging

Suggest creatinine clearanceDeterioration of renal impairmentSuggest glucoseSuggest PSASuggest full blood count and INRRepeat after overnight fastUnlikely to be CKDSuggest renin, aldosteroneSuggest protein electrophoresis?DiabeticeGFR suggests severe CKD (stage 4)

Case 11-03 Renal

Patient ID 3 years & 10 months old girl


Clinical Notes on Request FormFebrile. Nephrectomy for Wilm’s tumour 2.5 years ago.

Case DetailsSerum Sodium 139 mmol/L (132–143)

Potassium 5.0 mmol/L (3.5–5.0)Glucose 4.6 mmol/L (3.0–5.5)Bicarbonate 17 mmol/L (17–30)Urea 6.9 mmol/L (1.1–5.7)Creatinine 45 μmol/L (23–37)

Additional InformationC-reactive protein 110 mg/L (< 8.0)Previous serum creatinine 27 μmol/L 18 months ago (reference interval 16–31 μmol/L)

Suggested CommentResults indicate renal impairment. An acute infective or inflammatory process is likely. Causes of acute deterioration in renal function including dehydration, urinary tract infection or drug toxicity should be excluded. Interference in the creatinine result (for creatinine assays based on Jaffe reaction), especially from cephalosporins, should be excluded. In a child of this age, age-specific creatinine is a guide only, and an estimation of glomerular filtration rate (eGFR) will improve assessment of renal function.

Rationale The important finding here is of renal impairment in a child already at risk with a history of solitary kidney and Wilm’s tumour. The rise relative to the reference interval since the previous test suggests this is not due to the previous nephrectomy, but represents a new disease process. The clinical notes and markedly elevated C-reactive protein (CRP) suggest an acute infective/inflammatory process is likely. Thus in the first instance, causes of acute renal deterioration including dehydration, urinary tract infection or drug toxicity should be excluded. It is important to recognise that in a child with a history of previous illness may still be small for age. For these patients, age-based creatinine reference intervals are only a guide and the GFR may be lower than the creatinine suggests.

There is limited data in estimating GFR in children with solitary kidney, using either the modified Schwartz formula or cystatin C-based formulas; however the relationship appears no worse than in the general paediatric population. The KDOQI guidelines for evaluating kidney disease in children and adolescents recommend estimation of GFR using a creatinine-based formula (1). The guidelines also recommend a first morning urine specimen for protein:creatinine ratio, although random specimens are acceptable, for assessment of proteinuria. Some medications may interfere with creatinine result obtained from assays based on Jaffe reaction, and should be enquired for, especially cephalosporins. Specific to children with a history of Wilm’s tumour, a survey suggests renal failure is a rare (<0.26%) complication in children with unilateral nephrectomy (2); the more frequent causes of kidney failure in that group include Denys-Drash syndrome (in males; pseudohermaphroditism and diffuse mesangial sclerosis), progressive tumour in the remaining kidney, radiation nephritis and other causes, including hyperfiltration injury.

References

1. Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification and stratification. Pediatrics 2003:111:1416-21.

2. Ritchey ML, Green DM, Thomas PR et al. Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 1996;26:75-80.



Renal failure ?acute ?chronicDeterioration renal function compared to

previous urea and electrolytesImpaired renal function?Pre-renal renal impairment?Dehydration ?secondary to infection?Urinary tract infection?Infection/sepsis?Cephalosporin interference - JaffeSuggest urine microscopy, culture and sensitivity/casts/crystalsSuggest urine creatinine/protein/

albumin/microalbuminSuggest ultrasound of kidney/lower abdomen

Suggest monitor renal function test, calcium and liver function tests

Estimate eGFR - Schwartz formulaExclude pyelonephritisSuggest urine protein/creatinine ratio -

a.m. sample?Trimethoprim blocking creatinine

excretion?Tumour recurrence

Elevated urea and/or creatinineElevated C-reactive protein?InflammationFebrile statusSuggest full blood examination/ESRFurther investigation requiredLow to low normal bicarbonateSuggest referral to specialistAcidosisSuggest timed urine protein/creatinine

clearanceSuggest arterial blood gasesBorderline hyperkalaemiaMetabolic acidosisHigh normal potassiumSuggest blood cultures?Nephritis?Radiation adverse effects?Medication history?Intrinsic renal disease?Extrinsic renal disease?Recent meat intakeLow creatinine/urea ratioExclude glomerulonephritis?Chemotherapy adverse effectsHyperkalaemiaSuggest referral to emergency

department/admissionReduced eGFRSuggest urine electrolytesWilm’s tumour - urogenital malformation?HyperventilatingSuggest loss of heterozygosity

karyotyping for Ip/16q?Blood pressure statusConsider empiric antibioticsUnable to calculate eGFR due to age?Previous tx related impairment renal

failureRecommend rehydrationSuggest intravenous pyelogramExclude tumour lysis?WAGR (Wilms’ tumour, aniridia,

genitourinary anomalies, and mental retardation ) syndrome

?Long term complication of one kidneySuggest CT scan of remaining kidneyIf renal failure persists - renal imagingAggressive management and phone GP

Suggest repeat tests when patient wellSuggest renal biopsy?Denys-Drash syndrome?Compensatory hypertrophy of kidneySuggest tumour markers e.g. CEASuggest serum am cortisolSuggest immunoglobulinsSuggest chest CT scanSuggest IGF-IISuggest coagulation studies

Case 11-07 Renal

Patient ID 26-year-old man, refugee clinic


Clinical Notes on Request FormGeneralised oedema, eosinophilia

Case DetailsFasting serum Sodium 138 mmol/L (137–145)

Potassium 4.6 mmol/L (3.5–4.9)Chloride 101 mmol/L (100–109)Bicarbonate 27 mmol/L (22–32)Glucose 5.2 mmol/L (3.2–5.5)Urea 5.8 mmol/L (2.7–8.0)Creatinine 63 μmol/L (50–120)Urate 0.63 mmol/L (0.15–0.45)Phosphate 1.62 mmol/L (0.65–1.45)Total Calcium 2.10 mmol/L (2.10–2.55)Albumin 7 g/L (34–48)Protein 37 g/L (65–85)Total Bilirubin 2 μmol/L (2–24)GGT 51 U/L (<60)ALP 88 U/L (30–110)ALT 37 U/L (<55)

Additional InformationFasting serum Cholesterol 23.7 mmol/L (<5.5) (desirable)

Triglyceride 7.5 mmol/L (0.3–2.0)

Suggested CommentSevere hypoalbuminaemia and hyperlipidaemia in the clinical setting of oedema consistent with nephrotic syndrome. In view of the history of refugee status and the eosinophilia, helminthic parasites are a likely aetiology. Recommend urine protein/creatinine ratio and faecal microscopy.

RationaleSevere hypoalbuminaemia and hyperlipidaemia with oedema are typical signs of nephrotic syndrome. The lack of gastrointestinal symptoms and presence of hyperlipidaemia make a protein-losing enteropathy unlikely. There are many causes of nephrotic syndrome but the history of refugee status and presence of eosinophilia raise the possibility of parasitic infestation as the cause.

Helminthic parasites such as strongyloides, filariae, schistosoma and echinococcus are more commonly associated with eosinophilia than other parasites. Initial investigations should focus on the cause of hypoalbuminaemia. A spot protein/creatinine and/or albumin/creatinine ratio will confirm the presence of macroalbuminuria and form the basis for subsequent monitoring. A 24 h urine protein collection will help clarify nephrotic range proteinuria. Faecal microscopy may help identify a parasitic cause if this is present.

References1. van Velthuysen ML, Florquin S. Glomerulopathy associated with parasitic infections. Clin Microbiol

Rev 2000;13:55-66.2. Mawhorter SD. Eosinophilia caused by parasites. Pediatr Ann 1994;23:405,409-13.



Severe hypoproteinaemiaSevere hypoalbuminaemiaMarked hyperlipidaemiaLiver enzymes normalGeneralised oedemaEosinophilia?Nephrotic syndromeSuggestion of nephrotic syndrome?Parasitic infestation?HBV/HIV/syphilis/hepatitis?Protein-losing enteropathySecondary lipid abnormalitiesSuggest referral to specialistSuggest 24 h urine protein/albuminUrine protein/creatinine ratioSuggest stool examination ?Infiltrations

HyperlipidaemiaHyperuricaemiaHypoalbuminaemiaHypoproteinaemiaAllergies/inflammation/autoimmuneSuggest hepatitis/parasite serology?Malnutrition/malabsorptionCheck full blood examination/ film/ PT/

Coagulation?Drug relatedSuggest serum and urine electrophoresisHyperphosphataemiaSuggest autoimmune markers?Viral/chronic infection?Haematological malignancyUrgent medical attention requiredSuggest faecal alpha 1 antitrypsinSuggest ionised calcium?Diabetes/hypertension?Glomerular diseaseSuggest examine urinary sedimentIncreased cell turnoverAssociated with renal dysfunction?Liver disease/failureInterference from lipaemia?Renal biopsy if indicatedSuggest thyroid function tests?Renal diseaseRepeat glucoseSuggest urine microscopy and culture?HypothyroidismAdjusted calcium highSuggest urea/creatinine/creatinine

clearance?Post-streptococcal glomerulonephritisBorderline low calciumCheck urine lipiduria?Dilutional due to oedemaSuggest electrolytes with direct ISE method

?Sickle cell anaemiaSuggest CRP Repeat albumin/protein

Primary lipid disorder not excludedSuggest PTH?Inherited analbuminaemia?Gout / increased salt intake / Lesch-Nyhan syndrome

Suggest cardiac risk analysisDiabetes mellitus unlikely?Cushing's disease?Thyrotoxicosis?Decreased synthesis

Case 12-10 Renal



Clinical Notes on Request FormNewly diagnosed with diabetes mellitus

Case DetailsSample: Random spot urineTime: 2:00 pmAlbumin:creatinine ratio 5.5 mg/mmol creatinine (<3.5)

Additional InformationHbA1c 7.4%HbA1c (IFCC) 57 mmol/mol

Suggested CommentMild elevation of urine albumin:creatinine ratio in a newly diagnosed patient with diabetes. Random collection noted; first morning void collections are recommended to exclude exercise and posture effects. Sample collection should also avoid acute heavy exercise within 24 hours, febrile illness, nonsteroidal anti-inflammatory drugs, menstruation and vaginal discharge. Two of three positive samples within three months are required for diagnosis.

Rationale Urine albumin:creatinine ratio (ACR) is the preferred test for assessing proteinuria in diabetic patients. As this is a newly diagnosed case at age 40, it is likely that this is type 2 diabetes and it is appropriate to test for ACR at the time of diagnosis. For a diagnosis of persistent albuminuria there is a requirement for at least two out of three separate collections to be positive. This is due to the high within-subject biological variation of ACR (CVi 30–60%) as well as the many causes of false positive results.

The laboratory is in a good position to advise on appropriate sample collection. The preferred specimen is a first morning collection with avoidance of acute heavy exercise within 24 hours, febrile illness, nonsteroidal anti-inflammatory drugs, menstruation or vaginal discharge. Other factors which can increase urine albumin excretion but which may not be able to be controlled are congestive cardiac failure and some drugs, especially ACE inhibitors and angiotensin II receptor blockers (ARBs).

The use of timed urine collections, either overnight or 24 hour is not required, but it is recommended to use gender-specific cut points (<3.5 mmol/mg for women and <2.5 mg/mmol for men) to provide an approximate correction for the increased creatinine output in men. There are many factors that must be managed for a patient with newly diagnosed diabetes, and it is not possible to cover them all in a comment attached to a urine ACR. The comment should focus on the interpretation and responses to this specific test, as laboratories are generally unaware of the other factors that may influence management.

References1. Martin H. Laboratory measurement of urine albumin and urine total protein in screening for proteinuria

in chronic kidney disease. Clin Biochem Rev 2011;32:97-102.2. Royal Australian College of General Practitioners (RACGP). Guidelines for preventive activities in

general practice. 6th edition. Melbourne: RACGP; 2005.



Borderline raised ACRConfirm microalbuminuria Exclude transient microalbuminuriaSuggest repeat spot early morning urine

(1st void) for testSuggest repeat ACRConfirm 2/3 urines in 3–6 months

ACR>3.5Exclude fever/urinary tract infection/exercise/menses

Exclude diabetic nephropathyExclude heart failureIf eGFR >60 then cardiovascular disease

risk lowADS recommends ACR<3.5Urine ACR unreliable, collected at 2 pmExclude pregnancy

Suggest glycaemic control and reviewSuggest serum urea and electrolytes,

creatinineSuggest eGFRResults suggest microalbuminuriaExclude hypertension/check BPADS recommends HbA1c ≤7.0Elevated urinary albuminHbA1c result confirms diabetesElevated ACRSuggest lipid/HDL profile and

monitoringSuboptimal glycaemic controlPatient at risk of cardiovascular diseaseHbA1c target of <6.0% desirable?Degree of renal damagePersistent raised ACR - nephropathyAssess cardiovascular disease risk factorsCheck weight/BMI/dietSuggest lifestyle modificationExclude poor glycaemic controlSuggest liver function testsSuggest thyroid function tests?Chronic kidney diseaseIf microalbuminuria - treatment advisedSuggest urine collection – fasting and

supineSuggest retinal screeningSuggest foot screening?High ACR due to low muscle mass?Weight loss?Polydipsia/polyuria?Family history of diabetesExclude smoking

Suggest follow up testing annuallyConfirm diabetes mellitusSuggest 24 h urine proteinSuggest fasting glucose monitoringMicroalbuminuria clinically significantChronic kidney disease indicatedSuggest repeat HbA1cSuggest 24 h urine for albuminTest >2 h postprandialHb variants can affect HbA1c valueSuggest endocrine/diabetes reviewSuggest overnight urine albumin collection

Goal for Type II DM HbA1c <6.5%


Suggest therapy e.g. ACE inhibitorSuggest repeat urine albumin when HbA1c <6.0%

HbA1c shows good diabetic control

Case 14-02 Renal



Clinical Notes on Request FormFeeling run down; past medical history unremarkable.

Case DetailsSodium 138 mmol/L (134–145)Potassium 5.1 mmol/L (3.4–5.0)Urea 34.1 mmol/L (3.0–7.0)Creatinine 256 µmol/L (44–80)eGFR 21 mL/min/1.73m2

Additional InformationThyroid function tests were within normal limits.Full blood count showed a haemoglobin of 9.7 g/dL (11.5–16).Red cells were normochromic normocytic.A repeat electrolytes, urea, creatinine was performed, and was essentially similar.

Suggested CommentSerum creatinine and eGFR indicates severe reduction in renal function. In view of coexistent anaemia, chronic kidney disease (CKD) is likely, however, exclusion of causes of acute renal failure is recommended. Urgent referral to a nephrologist is recommended with additional testing for fasting glucose, lipids, bicarbonate, calcium, phosphate, parathyroid hormone (PTH) and spot urine albumin. Blood pressure should be checked and haematuria assessed using a urine dipstick.

Rationale A persistent eGFR between 15 and 29 mL/min/1.73m2 constitutes stage 4 chronic kidney disease (CKD). While the requirement for the definition of CKD is two tests greater than three months apart, referral to a nephrologist should be performed urgently in view of the age of the patient, and lack of information on the rate of progressive decline in renal function. Further investigations may be performed in the meantime to look for common related conditions, which may be the cause/consequence of CKD, or interact with CKD to increase morbidity/mortality. Anaemia of CKD is related to both reduced erythropoietin production by the kidney and resistance to the action of erythropoietin. High blood pressure is both a cause and an effect of CKD, and should be detected early and treated. Diabetes is a common cause of CKD and, if present, should be treated rigorously, but would also impact on the management of other aspects of CKD.

CKD constitutes a significant risk factor for cardiovascular events and death; an absolute risk approach is recommended. Changes in metabolism of calcium, phosphate, parathyroid hormone (PTH) and vitamin D typically start to occur once GFR is <60 mL/min/1.73m2, and are associated with an increased risk of fracture and increased cardiovascular mortality.

Haematuria, if present, could be consistent with glomerulonephritis. Renal ultrasound may be considered to exclude structural abnormalities as a cause of chronic kidney damage.

Reference1. Kidney Health Australia. http://www.kidney.org.au



Severe renal function impairmentCoexistent anaemiaChronic kidney disease is likelyConsistent with stage 4 chronic renal

failure?Proteinuria/suggest spot urine albuminSuggest calcium/phosphate

(PO4)/parathyroid hormone (PTH)Suggest microscopy and cultureSuggest urine albumin/creatinine ratioSuggest fasting glucoseReview medications/drugsCheck blood pressure?Urinary tract infection/ pyelonephritis/

polycystic kidney disease/ drug toxicMild hyperkalaemiaUrgent referral to nephrologist

recommendedAssess haematuria?DiabetesSuggest electrolytes, urea, creatinine,

bicarbonate?HypertensionSuggest HbA1cSuggest lipidsHigh potassium secondary to reduced

renal functionAvoid nephrotoxic agentseGFR needs to be elevated >3 months?Glomerulonephritis/vasculitis/acute

tubular necrosis

Suggest renal imaging?Acute renal injury/failureRaised urea and creatinineLow eGFRSuggest protein/albumin/liver function

testsMonitor kidney functionExclusion of causes of acute kidney

injury recommendedConfirm with repeat sampleSuggest clinical assessment?Family history kidney diseaseRepeat tests twice in next 3 monthsSuggest iron studiesSuggest repeat urea/creatinineLow haemoglobinSuggest 24h proteinAssess volume statusConfirm eGFRSuggest C-reactive protein

Suggest 24h urine electrolytes/ urea/ creatine/calcium/PO4

?Systemic lupus erythematosusSuggest serum and urine osmolality?Dehydration?eGFR unreliable due to body size/dietSuggest hCG to exclude pregnancy?Cardiac muscle damageSuggest urine myoglobin?Synthetic cannabis useSuggest renal biopsySuggest CK/CKMB?Pre-renal cause?Acute blood lossSuggest erythropoietin levelsScreen for ANA/ANCA/GBM antibodies


?Stage 3 chronic kidney diseaseSuggest bone marrow studies

Case 14-03 Renal



Clinical Notes on Request FormPresents with malaise and generalised muscle pain. No medications.

Case DetailsNa 136 mmol/L (135–145)K 6.0 mmol/L (3.5–4.5) Cl 104 mmol/L (98–108) HCO3 25 mmol/L (23–33) Urea 16.5 mmol/L (3.0–8.0) Creatinine 180 µmol/L (60–120) Glucose (random) 9.5 mmol/L (3.0–5.5)

Suggested CommentDisproportionately raised potassium with chronic kidney disease (CKD) stage 3b (eGFR: 32 mL/min/1.73m 2) in an elderly person with hyperglycaemia is suggestive of hyporeninaemic hypoaldosteronism. Please repeat urgently on a plasma sample to confirm potassium and renal status. Recommend further investigation with fasting glucose, creatine kinase, morning cortisol, renin and aldosterone and urine albumin (first morning void). NB acute causes for reduced GFR should be excluded.

Rationale Effective renal excretion of potassium is typically maintained until the eGFR falls below ~15 mL/min, i.e. stage 5 chronic kidney disease (CKD). Hence this elevation in potassium is higher than expected for this degree of renal impairment. Pseudohyperkalaemia should be excluded by urgent repeat testing. Syndrome of hyporeninaemic hypoaldosteronism is a relatively common but often overlooked cause of hyperkalaemia with some authors suggesting it may account for 10% of all cases of hyperkalaemia. The typical patient is an elderly with diabetes mellitus; often the syndrome is triggered by stressors such as dehydration, acute illness or the introduction of medications such as non-steroidal anti-inflammatory drugs or angiotensin converting enzyme inhibitors (although this patient was stated not to be on medications).

Once true hyperkalaemia is confirmed, adrenal insufficiency should be excluded and renin/aldosterone evaluated. A reduced GFR at any age is indication for investigation and follow-up. Acute reduction in GFR must always be excluded. The CKD management guidelines (2012) are available at www.kidney.org.au and provide guidance on response to a first abnormal result (repeat with albumin:creatinine ratio within 2 weeks) as well as guidance for further testing and treatment based on both the eGFR and the albumin:creatinine ratio.

References1. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1041-2.2. Hollander-Rodriguez JC, Calvert JF Jr. Hyperkalemia. Am Fam Physician 2006;73:283-90.



Critical hyperkalaemiaPotassium is higher than expectedRenal impairment and with

hyperkalaemiaHigh urea, creatinine and potassium

consistent with CKDeGFR 32 mL/min consistent with stage

3b CKD if present for 3 monthseGFR suggest stage 3 CKDModerate renal dysfunction?Acute renal failure?Acute/chronic kidney diseaseExclude pseudohyperkalaemiaSuggest repeat electrolytes/bicarbonate Check potassium on both heparin and

serum samplesSuggest eGFRModerate hyperglycaemia?Hyporeninaemic hypoaldosteronismIncreased risk of diabetesSuggest fasting glucose/HbA1cSuggest GTTSuggest creatine kinase to assess muscle

painSuggest urine albumin:creatinine ratio/

protein/ microalbumin?Diabetes mellitusSuggest repeat serum creatinine, urea and

glucose?Adrenal insufficiency/Addison'sSuggest morning cortisolSuggest aldosterone/reninSuggest synacthen stimulation testSuggest full blood count and plateletsUrgent clinical reviewKidney injury secondary to type 2

diabetes mellitus (DM)Check for previous resultsRefer to www.kidney.org.au?RTA type 4Exclude acute causes for reduced GFR

Suggest urinalysis/culture and sensitivityIncreased random glucoseCheck and monitor blood pressureIncreased potassium, urea and creatinineSuggest calcium, phosphate, vitamin D,

parathyroid hormone, magnesium, ironSuggest renal ultrasound/imagingSuggest fasting lipidsSuggest thyroid function tests?RhabdomyolysisSuggest liver function testsSuggest electrocardiogramLow sodium /high potassium?DehydrationAssess cardiovascular disease risk factorsSuggest CK, CKMB, myoglobin, AST,

troponin ICheck specimen for haemolysisSuggest C-reactive protein/autoimmune

testing?Metabolic/inflammatory/malignancyReview of medicationsNormal sodium/chloride?Family history of kidney diseaseHbA1c not Medicare rebatable?Low insulin?Renal failure?Glomerulonephritis?LupusOffer advice on lifestyle changeSuggest arterial blood gasCalculated osmolarity: 310 mmol/kgRenal failure risk factors:

>60y/obese/smokerPrerenal cause of renal dysfunctionMild hyperkalaemia

Hyperkalaemia due to renal impairmentRefer nephrologist/urologistSuggest plasma and urine electrophoresisCARA guide-31 eGFR is stage 4/5eGFR indicates advanced CKDSuggest serum/urine osmolalitySuggest viral serology


Check creatinine after 6–12 weeks?Aging kidney

Case 6-04 Ca/Mg/Phos



Clinical Notes on Request FormCramps

Case DetailsSodium 142 mmol/L (136–145)Potassium 4.3 mmol/L (3.5–5.1)Bicarbonate 29 mmol/L (21–32)Urea 5.6 mmol/L (2.0–8.5)Creatinine 0.1 mmol/L (0.06–0.11)Total Protein 75 g/L (60–80)Albumin 45 g/L (35–52)Bilirubin 15 μmol/L (<21)ALT 21 U/L (0–40)Gamma GT 14 U/L (12–64)Alk Phos 67 U/L (<110)Calcium, adjusted 1.55 mmol/L (2.10–2.60)Phosphate 1.8 nmol/L (0.8-1.5)

Suggested CommentThe severe hypocalcaemia and the mild hyperphosphataemia in the presence of normal renal function suggest hypoparathyroidism. Suggest repeat calcium together with PTH, and also exclude hypomagnesaemia.

Rationale The low calcium and high phosphate in the absence of renal failure suggest hypoparathyroidism. To exclude other causes of hypocalcaemia, the measurement of 25-OH vitamin D, magnesium and a clinical history would be useful. The most likely causes for hypoparathyroidism are post neck surgery and autoimmune disease.

Reference1. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-75.



?HypoparathyroidismPTH deficiency?Clinical historySuggest PTHSuggest magnesium?Hypomagnesaemia

HypocalcaemiaRaised phosphateSuggest vitamin DCheck ionised calciumNormal renal function?Vitamin D deficiency?Other causes?Pseudohypoparathyroidism?Drugs/medicationsSuggest thyroid function testsLow corrected calciumPhone to discuss with doctorNormal ALPConsider calcium replacementSuggest other testContamination unlikelySuggest parathyroid antibodiesNormal albumin

Suggest 24h urine calcium/phosphateSuggest amylase/lipase?Acute pancreatitisTetany suggested?Artefactual causesSuggest CKSuggest acute referralSuggest creatinine clearance?Hyperparathyroidism?Renal diseaseHypercalcaemia?Vitamin D intoxicationSuggest calcitoninSuggest ALP isoenzymesSuggest osmolality



Patient Location Surgical Ward

Clinical Notes on Request FormPost-colectomy

Case DetailsSodium 146 mmol/L (136–146)Potassium 3.6 mmol/L (3.5–5.0)Urea 4.0 mmol/L (2.7–8.0)Creatinine 50 µmol/L (60–110)Calcium 2.1 mmol/L (2.2–2.6)Phosphate 0.2 mmol/L (0.8–1.4)Albumin 31 g/L (35–50)

Additional InformationPre-operative biochemistry unremarkable.

Suggested CommentSevere hypophosphataemia may indicate phosphate depletion, possibly accentuated by refeeding. Consider urgent parenteral supplementation.

Rationale Phosphate is the most abundant intracellular anion and only <0.1% is found in the extracellular fluid. Serum measurement of phosphate is not a sensitive reflection of intracellular stores. Hypophosphataemia is a relatively common abnormal biochemistry finding among hospitalised patients. These are usually mild and self-limiting.

Hypophosphataemia can be caused by intracellular shifts driven by insulin, catecholamine or alkalosis, such as refeeding syndrome, recovery from diabetic ketoacidosis, respiratory/ metabolic alkalosis, and glucose or insulin administration. It may also be due to decreased intestinal absorption, such as vomiting, diarrhoea, malabsorption/malnutrition, and vitamin D deficiency. Lastly, an increase in renal excretion may precipitate hypophosphataemia, for example in primary/secondary hyperparathyroidism or disorders of renal handling (e.g. Fanconi’s syndrome, hypophosphataemic rickets, oncogenic osteomalacia). In acute care setting, severe hypophosphataemia is associated with alcoholism and refeeding without phosphate replacement.

In this case there is no evidence of long-standing hypovitaminosis D or renal phosphate wasting and an acute mechanism should be suspected. Severe hypophosphataemia leads to central nervous system effects (irritability, somnolence), cardiac dysfunction and rhabdomyolysis. In the presence of rhabdomyolysis the phosphate level increases again.

References1. Singhal PC, Kumar A, Desroches L, et al. Prevalence and predictors of rhabdomyolysis in patients with

hypophosphatemia. Am J Med 1992;92:458-64.2. Troup S. Phosphate monograph. http://www.acb.org.uk/Nat%20Lab%20Med%20Hbk/Phosphate.pdf



Marked hypophosphataemiaPhone results?On total parenteral nutrition?Refeeding syndrome?Malabsorption post-colectomy?Gastrointestinal tract loss?Respiratory alkalosis?Phosphate loss/sequestrationSuggest repeat/monitor levelsSuggest phosphate replacementSuggest other electrolytes/ vitamins/

protein testsSuggest magnesiumRisk of myopathy and associated

problemsRisk of rhabdomyolysisSuggest assess acid-base?IV glucose?Intracellular shift with glucose load?Parenteral nutrition without phosphate

?MalnutritionCorrected calcium okayHypoalbuminaemia?Renal losses?Drug effectSuggest calcium/phosphate excretion

studies?AlcoholismSuggest ionised calcium / corrected

calciumSuggest PTHCheck glucoseRefer to pathologistLow albumin ?due to acute response?Artefact?Hyperparathyroidism?Acid-base imbalanceSuggest nutritional reviewSuggest clinical review?Magnesium deficiencyLow normal potassiumHistory of post-colectomyLow creatinineMay not reflect cellular phosphateHigh normal sodium?Aldosterone activation

Hypocalcaemia?Sepsis?Due to pre-op preparation?IV overhydration?Treated diabetic ketoacidosisSuggest creatine kinase?Liver diseaseSuggest troponin/BNP/ECG?Magnesium supplementation?Neuroleptic malignant syndromeGenerally unremarkableNo comment on this case?Recovery from burnsSuggest calcium replacement?On respiratory ventilation?Cardiac event




Clinical Notes on Request FormFamily history of hypercalcaemia.

Case DetailsSerum

Na 139 mmol/L (135–145)K 4.5 mmol/L (3.5–5.0)Cl 103 mmol/L (96–109)Bicarbonate 31 mmol/L (23–32)Urea 5.8 mmol/L (3.5–7.5)Creatinine 95 μmol/L (40–120)Calcium 2.64 mmol/L (2.10–2.60)Phosphate 0.7 mmol/L (0.8–1.5)Albumin 48 g/L (35–50)PTH 5.0 pmol/L (1.6–6.9)

Fasting Spot UrineUrine Calcium <0.30 mmol/LUrine Creatinine 1.5 mmol/LCalcium/Creat. Ratio <0.20 mol/mol

Suggested CommentSuggest check ionise calcium, repeat plasma phosphate (fasting) and consider 24 hour urine calcium/creatinine clearance ratio to investigate for possible familial hypocalciuric hypercalcaemia.

Rationale Familial hypocalciuric hypercalcaemia (FHH) is a rare (1:70,000) autosomal dominant inherited condition caused by heterogeneously distributed inactivating mutations within the calcium sensing receptor (CASR) gene. It is characterised by persistent asymptomatic hypercalcaemia, relatively low urine calcium and inappropriately normal or elevated parathyroid hormone. It is important to differentiate FHH from primary hyperparathyroidism as the former requires no specific treatment while the latter requires surgery.

A variety of methods have been advocated to adjust serum total calcium to estimate ionised calcium but all have their limitations. It is advisable to measure ionised calcium directly to clarify the diagnosis in this case. In the setting of hypercalcaemia, either a 24 h urine calcium:creatinine clearance ratio [Ca/CrCl, (24-h U-calcium/P- calcium, total)/(24-h U-creatinine/P-creatinine)] of <0.01 or a fasting urine calcium excretion (CaE) of <30 μmol/L GFR are consistent with the diagnosis of FHH. The use of either a spot urine calcium or spot urine calcium/creatinine ratio is insufficiently robust for diagnostic purposes.

The mutations associated with FHH are widely distributed in the extracellular calcium sensing or the signal transduction domain of the CASR gene, so targeted genetic testing is insufficient for diagnosis. The relatively low serum phosphate appears incongruous with FHH and assessment of a repeat serum/plasma phosphate and urine TmPi is advisable, as mild primary hyperparathyroidism is also possible in this case and urine Ca/CrCl or CaE can overlap in both conditions. Ultimately, in some cases, family studies of serum ionised calcium and urine Ca/CrCl may still be required.

References

1. Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003;33:598-603.

2. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008;69:713-20.



Consistent with familial hypocalciuric hypercalcaemia (FHH)

?Familial hypocalciuric hypercalcaemiaConsistent with familial hypercalcaemic

syndromeSuggest ionised calciumRepeat phosphate Suggest 24h urine calcium

Mild hypercalcaemiaUrinary calcium lowHypophosphataemiaFamily history of hypercalcaemia?Primary hyperparathyroidismNormal PTH levelInappropriately normal PTHCorrected calcium normalFHH asymptomatic, benign conditionSuggest magnesiumDue to calcium sensing receptor (CASR)

gene mutationSuggest repeat testingAutosomal dominant conditionSuggest vitamin D?Multiple endocrine neoplasia (MEN) 1

or 2aPTH top end reference rangeUrine dilute, low creatinineSuggest thyroid function testsSuggest family screeningSuggest ALPNormal renal function?Drug induced hypercalcaemiaUrine Ca/Cr diagnosis of FHH or l° hyperparathyroidismCa/Cr ratio difficult to interpretLow calcium/creatinine clearanceRepeat non-fast, no tourniquet?Malabsorption, renal loss, alkalosis?Familial hyperparathyroidism?Excess vitamin DParathyroidectomy contraindicatedLow PO4 ? intake/antacids/non-fastingRepeat PTHNo commentNeed clinical historyFHH requires no treatmentInappropriate PTH or PHrP secretionSuggest endocrinology review?l° hyperPTH + vitamin D deficiency?Fasting sample

Suggest genetic testing for CASR?NeoplasmSuggest parathyroid scanFHH may lead to hyperCa crisisHyperparathyroidism unlikelySuggest succinic dehydrogenase mutationConsistent with hypoparathyroidism?Milk-alkali syndrome?Chrondrocalcinosis, gall stonesSuggest calcitonin?Hypocalciuria 2° to PTHRenal impairment not excludedSuggest PHrPSuggest 1,25 OH vitamin D



Patient Location Endocrine Clinic

Clinical Notes on Request FormMuscular dystrophy. ? Disuse bone loss

Case DetailsFasting morning spot urine

Creatinine 3.8 mmol/LCalcium 3.37 mmol/LN-Telopeptide 404 nmol BCE/LCalcium/Creatinine 0.89 mol/mol (0.10–0.58)N-Telopeptide/Creat. 106 nmol BCE/mmol (<50)(BCE = Bone Collagen Equivalents)

Additional InformationPlasma

Calcium, Adjusted 2.51 mmol/L (2.15–2.60)Phosphate 1.00 mmol/L (0.80–1.50)Creatinine 29 μmol/L (45–90)Alkaline Phosphatase 84 U/L (35–135)PTH 3.3 pmol/L (0.7–7.0)25-OH Vitamin D 107 nmol/L (>50)

Suggested CommentLow muscle mass and the resultant low creatinine production makes interpretation of the urine creatinine ratios unreliable. A 24 h urine sample or fractional excretion is suggested to estimate renal calcium losses. A bone turnover marker in serum or in a 24 h urine sample is recommended in place of N-telopeptide/creatinine ratio.

Rationale The use of creatinine ratios for analytes in urine is commonly used with the aim of reducing the effect of hydration on the analyte concentration. This process however introduces an additional variability due to between-person differences in the rate of creatinine production, which is directly proportional to the muscle mass of the patient. This process is generally robust but may produce misleading results in patients with extremes of muscularity.

Subjects with a large muscle mass will produce lower results for urine analytes after creatinine correction and subjects with low muscle mass will give elevated results. In this case there are three pieces of evidence that the patient has a low creatinine production and therefore creatinine correction may produce spuriously elevated results. These factors are the history of muscular dystrophy, the very low serum creatinine and the low urine creatinine concentration. Of these, the serum creatinine of 27 μmol/L is the strongest indication of the very low muscle mass.

The key feature in this case is to identify this effect and not proceed with an inappropriate interpretation. This effect was not recognised in over half the responses with consequent inappropriate interpretations. In order to obtain the information sought with these requests it is necessary to use tests that are not affected by the creatinine, such as timed urine collections or serum tests.



Low creatinine/muscle wastingRatios false 2° to low creatinineNormal plasma ALPSuggest 24h urine calciumSuggest P1NPSuggest 24h urine NTxSuggest C-TelopeptideSuggest serum osteocalcinSuggest calculate fasting urine Ca

excretionSuggest serum NTxSuggest P1CP

Increased bone resorption/lossHigh urine NTx/creatinine ratioSuggest BMD scanHigh urine NTxHigh calcium/creatinine ratioBone resorption/osteoporosis due to

immobilisation?OsteoporosisHypercalciuriaSuggest TSH/TFTNormal vitamin D/adequate

supplementation.NTx marker of increased bone resorptionNormal PTH?Glucocorticoid Rx?HyperthyroidismNormal plasma calciumNormal plasma phosphate?Antiresorptive Rx?Calcium/vitamin D supplements?Increased NTx 2° circadian

variation/exerciseSuggest sequential bone mineral markersResults consistent with muscular

dystrophy?Menstrual variation/menopauseDoes not support disuse bone lossNo comment?Preanalytical/sample collection factors?Drug effectCheck dietary calcium intakeCollect fasting 2nd void urine NTx?HypercalciuriaNTx not useful for osteoporosis diagnosis?Endocrine disorderHyperparathyroidism excludedPaget’s disease excludedBone demineralisation not increased

turnoverNormal calcium homeostasisSuggest CKElevated vitamin DLow plasma albuminSuggest bone formation markersSuggest tests to confirm bone lossSuggest TRACP5b

?Hyperparathyroidism?Metastatic bone diseaseConsider increase antiresorptive therapyConsider hypogonadism if very unwellIncreased risk fracturesConsider genetic cause/lifestyle?GIT disease?PregnancySuggest 24h UFC/?Cushing’sExclude multiple myeloma?Paget’s disease Suggest BALP, ICTPRefer to endocrine clinic




Clinical Notes on Request FormOsteoporosis. No medication.

Case DetailsFasting serum

Sodium 139 mmol/L (135–145)Potassium 4.2 mmol/L (3.5–5.5)Chloride 104 mmol/L (95–110)Bicarbonate 23 mmol/L (20–32)Urea 5.5 mmol/L (3.5–9.5)Creatinine 67 μmol/L (45–90)Total Bilirubin 5 μmol/L (3–15)ALP 124 U/L (30–115)GGT 31 U/L (5–35)ALT 23 U/L (5–40)Total Protein 77 g/L (63–80)Albumin 48 g/L (36–47)Globulin 29 g/L (23–39)Calcium 2.8 mmol/L (2.15–2.55)Phosphate 1.2 mmol/L (0.80–1.50)Calcium, Adjusted 2.73 mmol/L (2.20–2.60)25OH Vitamin D 36 nmol/L (75–250)PTH 4.1 pmol/L (1.6–6.9)

Suggested CommentMild hypercalcaemia and non-suppressed PTH is most likely due to primary hyperparathyroidism (PHPT). Familial hypocalciuric hypercalcaemia (FHH) and lithium therapy can also present with mild parathyroid-dependent hypercalcaemia. FHH should be excluded by reviewing previous results and estimation of either fasting urine calcium excretion or 24 h urine calcium creatinine clearance ratio. Mild vitamin D deficiency is common with PHPT and may exacerbate bone disease.

Rationale The degree of hypercalcaemia and the non-suppressed PTH in the context of investigation of osteoporosis indicate primary hyperparathyroidism is likely. A review of past results would be helpful in this case. Familial hypocalciuric hypercalcaemia (FHH) is a rare (1:70,000), autosomal dominant inherited condition characterised by persistent, asymptomatic hypercalcaemia, low urine calcium excretion and inappropriately normal/ elevated parathyroid hormone due to a mutation of the calcium sensing receptor (CASR) gene.

In the setting of parathyroid dependent hypercalcaemia two tests of urine calcium are helpful. A 24 h urine calcium clearance ratio involves assessment of serum calcium, serum creatinine, urine calcium and urine creatinine. A clearance ratio of <0.01 is typical in FHH and >0.02 is common in primary hyperparathyroidism. Note the clearance ratio [(24-h U-calcium/P- calcium, total)/(24-h U-creatinine/P-creatinine)] is not the same test as a urine calcium/creatinine ratio. Alternatively, a fasting urine calcium excretion (urinary calcium/ urinary creatinine × serum creatinine) of <30 μmol/L GFR is also consistent with FHH. The differentiation of FHH is important to prevent unnecessary surgical neck exploration. Since there are many mutations within the CASR gene, no single simple genetic test is available to exclude this diagnosis.



Mild hypercalcaemiaInadequately suppressed PTHMild vitamin D deficiency?Primary hyperparathyroidism?Hyperparathyroidism ?FHH?Drug history (Li or thiazides)Review previous resultsSuggest 24h Ca, Ca/creatinine ratio

Low vitamin DHypercalcaemiaNormal PTHSuggest ionised calciumMildly increased ALPSuggest vitamin D replacementRepeat calciumSuggest bone turnover/formation markersSuggest thyroid function testsRaised ALP due to bone formationRepeat PTHRepeat tests after vitamin D supplementRepeat collection with no stasisIncreased bone turnoverSuggest protein electrophoresis-serum,

urineConsistent with osteoporosis?Ca supplementationSuggest 1,25 dihydroxy vitamin DSuggest PTHrPSuggest bone mineral density scan ?Immobilisation?Paget’s diseaseModerate vitamin D deficiencySuggest serum magnesium?Hyperthyroidism?MyelomaRepeat testingRepeat 25-OH vitamin DSevere vitamin D deficiencyContribute to osteoporosisNormal phosphateSuggest full blood examinationNot typical vitamin D deficiencyRaised ALP 2° to vitamin D deficiency?Healing bone fracturesNormal renal functionAlbumin elevatedLow vitamin D due to inadequate

sunlightRepeat test with adequate hydration?Vitamin D dietary shortageSuggest parathyroid ultrasound scanLow vitamin D due to primary PHPT?Magnesium deficiency?Transient hypercalcaemiaSuggest genetic studies for FHH?OsteomalaciaRepeat on fasting specimenLow vitamin D prevents Ca absorption?Decreased intestinal absorption vitamin

DRepeat test before vitamin D supplementNot consistent with osteoporosis

?Malignancy?Sarcoidosis or TB?Hypercalcaemia age relatedHyperparathyroidism unlikelyPHPT excludedSuggest renal imagingSuggest ACESuggest chest X-ray?AcromegalySuggest X-rays for bone fractures?Secondary hyperparathyroidism?HyperglycaemiaNo vitamin D replacement?Hypothyroidism




Clinical Notes on Request FormNo history of fractures or falls.Strong family history of autoimmune disease and cancer.

Case Details25OH vitamin D 62 nmol/L

Additional InformationSerum

Creatinine 63 μmol/L (60–105)Calcium 2.32 mmol/L (2.15–2.65)Albumin 43 g/L (38–50)Calcium, Adjusted 2.30 mmol/L (2.15–2.65)Parathyroid Hormone 8.9 pmol/L (1.1–7.2)

Suggested CommentBorderline raised PTH with intact renal function, unremarkable adjusted total calcium and vitamin D is unlikely to be pathologically important.

Rationale Mildly increased parathyroid hormone with unremarkable adjusted total calcium and serum creatinine are frequent laboratory findings. Current published guidelines by ANZBMS and recent recommendations by the Institute of Medicine (IOM) both advocate adoption of a target threshold of 50 nmol/L for 25OHD (1, 2). The IOM committee was concerned about some laboratories reporting higher 25OHD target thresholds and there was an urgent need for consensus target thresholds reported by laboratories. Whilst a variety of diseases have been associated with vitamin D deficiency, randomised clinical trial data demonstrating the benefit of vitamin D supplementation in these groups are lacking (3). Although ionised calcium is more sensitive than adjusted total calcium in the diagnosis of early primary hyperparathyroidism, the adjusted calcium result makes this diagnosis unlikely in this case (4).

References1. Working Group of the Australian and New Zealand Bone and Mineral Society: Endocrine Society of

Australia; Osteoporosis Australia. Vitamin D and adult bone health in Australia and New Zealand: a position statement. Med J Aust 2005;182:281-5.

2. Slomski A. IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. JAMA 2011;305:453-6.

3. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer – ready for prime time? N Engl J Med 2011;364:1385-7.

4. Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003;33:598-603.



Vitamin D normalVitamin D deficiency unlikelyNormal calcium levelMild increase PTHNormal renal function?Bisphosphonate therapy

Elevated PTHSuggest Mg/Phos/ALPSuggest ionised calciumRepeat PTHSuggest 2° hyperparathyroidism?Malabsorption?Drug ?anticonvulsantsRepeat serum calcium?Adequate dietary calcium intakeSuggest repeat Ca/VitD/PTH after

supplementRepeat vitamin DStrong family history autoimmune

diseaseSuggest coeliac screening?Early hyperparathyroidismMild 2° hyperparathyroidismSuboptimal vitamin D level?Normocalcaemic hyperparathyroidism?Diuretic therapy?MalnutritionNo reference range given for vitamin DPTH assay interference to be excludedRepeat testing 3–6 monthsRepeat PTH in 3 months?Adequate vitamin DNormal corrected calciumSuggest renal panel/albumin?Chronic vitamin D deficiencySuggest fasting morning PTHSuggest fasting calciumFurther investigation requiredInterpret results with seasonsConsistent with mild physiologic vitamin

D deficiencySuggest diabetes screeningSuggest liver function testsRepeat fasting PTH at 8pm?D2, D3 or bothNo formal comment issuedPTH inappropriate for calcium levelSuggest review in 2–3 monthsNormal albumin

Suggest vitamin D supplementationIncreased risk cancer/autoimmune disease

Vitamin D lowSuggest 24h Ca/PO4 excretion?Primary hyperparathyroidismExclude adenoma/malignancy if clinically indicated

Due to family history increased vitamin D beneficial

Suggest thyroid screeningSuggest bone turnover markersSuggest urinary Ca/creatinine2° hyperparathyroidism unlikelyVitamin D indeterminate?Familial hypocalciuric hypercalcaemiaExclude MEN I and IISuggest full blood examination/ESRCheck renal functionSuggest total protein and protein electrophoresis

Suggest increase sunshine exposure/dietary intake

Recommend referral to specialistSuggest uric acid maybeSuggest calcium supplementation


?Bone densitometryMildly low PTH?Patient on vitamin D masking low vitamin D



Patient Location Hospital in-patient

Clinical Notes on Request FormIn hospital 4 months following head injury.

Case DetailsTotal Calcium 2.93 mmol/L (2.15–2.60)Albumin 38 g/L (35–50)Phosphate 1.46 mmol/L (0.8–1.50)Alkaline Phos 84 U/L (35–135)PTH 0.6 pmol/L (0.7–7.0)25OH Vitamin D 111 nmol/L (>50)

Additional InformationSodium 147 mmol/L (134–146)Potassium 3.5 mmol/L (3.4–5.0)Bicarbonate 32 mmol/L (22–32)Urea 8.7 mmol/L (3.0–8.0)Creatinine 69 μmol/L (60–110)eGFR >60 mL/min/1.73m2

Suggested CommentMild hypercalcaemia with suppressed PTH suggests hypercalcaemia of immobilisation given the history and the age of the patient. Dehydration exacerbates hypercalcaemia. Consider thyroid function tests to exclude thyrotoxicosis.

Rationale Immobilisation hypercalcaemia mainly results from rapid bone turnover and may be seen after spinal cord injury or long bone fracture in children and adolescents with growing bones and after cerebrovascular accident in the elderly, especially in the presence of high turnover states such as Paget’s disease. The exact mechanisms of immobilisation hypercalcaemia are unclear, but are not PTH-dependent. The generally accepted explanation is the loss of mechanical stress (mechanostat theory) leading to increased osteoclastic bone resorption and decreased bone formation, which are the hallmarks in bone biopsy.

The serum calcium level depends on the rate of bone resorption and the capacity of renal calcium excretion. The median interval between initiation and immobilisation and onset of hypercalcaemia is 4 weeks, but may be extended to 16 weeks in patients with normal renal function. In chronic renal insufficiency the interval is shortened and may range from 3 to 16 days. Hypercalcaemia itself can induce acute impairment of renal function via glomerular arteriolar vasoconstriction, volume depletion, and nephrocalcinosis and then in turn, compromise calcium clearance and accentuate the degree of hypercalcaemia. Other possible causes such as Grave’s disease may be considered, and rarely granulomatous diseases such as sarcoidosis.

Reference1. Cheng CJ, Chou CH, Lin SH. An unrecognized cause of recurrent hypercalcemia: immobilization.

South Med J 2006;99:371-4.



Mild hypercalcaemiaDue to immobilisationProlonged hospitalisationDue to excessive bone turnoverHyperparathyroidism unlikelyPTH independent/ non-parathyroidNot vitamin D mediated hypercalcaemiaSlightly increased urea?Dehydration Replacement fluid will decrease calcium ?HyperthyroidismSuggest thyroid function testsSuggest ongoing monitoringSignificant increased corrected calcium

HypercalcaemiaReduced PTHNeed to exclude malignancyRaised NaSuggest 24h urine calcium/ phos?Due to medications?Chronic granulomatous diseaseSuggest ionised calciumSuggest 1,25 vitamin D?SarcoidosisSuggest repeat total calcium/PTHSuggest N-telopeptide/bone markers?Diabetes insipidusSuggest urine osmolality/volume/NaNormal albuminHigh/normal phosphateNormal 25-hydroxyvitamin DSuggest cortisolNormal ALPSuggest ACTH/GH/FSH/LH/prolactin?Hyperaldosteronism?Increased renal retentionLow creatinineSuggest ALPSuggest serum/urine electrolytesElevated serum calciumSuggest clinical and radiological examSuggest magnesiumRenal cause unlikelyNormal creatinine/ eGFR?Increased 1,25 vitamin D intake

Suggest PTHrP?Familial hypocalciuric hypercalcaemia?Increased vitamin D intakeSuggest ACESuggest urine electrophoresis/ immunofixation

25OH vitamin D raised?SepsisSuggest vitamin AExclude factitious cause?Paget’s diseaseSuggest water deprivation test?RhabdomyolysisMild 2° hypoparathyroidism?Increased intestinal absorption?Hypothyroidism?Milk-alkali syndromeRecommend urgent consultation




Clinical Notes on Request FormPresents with back pain.

Case DetailsAlbumin 29 g/L (32–46)Calcium (Total) 2.60 mmol/L (2.15–2.55)Calcium (Adjusted) 2.83 mmol/L (2.15–2.55)Intact PTH 3.2 pmol/L (1.3–6.8)

Additional InformationIonised Calcium 1.27 mmol/L (1.12–1.32)Sample pH 7.41 (7.35–7.45)Ion Ca (pH-adjusted) 1.28 mmol/L (1.12–1.32)

Suggested CommentThe significant discrepancy between the ionised calcium measurement and the albumin-adjusted calcium suggests the possibility of an abnormal globulin binding to calcium; recommend serum and urine protein electrophoresis to investigate.

Rationale In normal physiology, approximately half of serum calcium exists in free (ionised) form while the other half is protein-bound, mainly to albumin. The direct measurement of ionised calcium plays an important role in the diagnosis of pseudohypercalcaemia. It is an infrequent but important condition in monoclonal gammopathy (e.g. multiple myeloma and Waldenström macroglobulinaemia), where monoclonal immunoglobulins cause raised total/albumin-adjusted calcium and normal ionised calcium.

Several method-dependent mechanisms may explain this apparent discrepancy. The paraproteins may act as carrier proteins in a similar fashion to albumin, causing increased binding of calcium. Paraproteins may also increase the solid phase of the serum, causing a 'water exclusion' effect and may affect indirect ion-selective electrode methods. Finally, paraproteins may precipitate during laboratory analysis, affecting photometric methods.

If ionised calcium measurement is not available, a simple two-time dilution or use of an alternate assay with different methodology may clarify the situation. Whilst pseudohypercalcaemia is uncommon, the clinical presentation of back pain and discrepant total calcium compared with ionised calcium justify further investigation for a possible paraproteinaemia in this case.

References1. Loh TP, Yang Z, Chong AT, et al. Pseudohypercalcaemia in a patient with newly diagnosed

Waldenstrom macroglobinaemia. Intern Med J 2013;43:950-1.2. Annesley TM, Burritt MF, Kyle RA. Artifactual hypercalcemia in multiple myeloma. Mayo Clin

Proc 1982;57:572-5.3. Schwab JD, Strack MA, Hughes LD, et al. Pseudohypercalcemia in an elderly patient with multiple

myeloma: report of a case and review of literature. Endocr Pract 1995;1:390-2.



Ionised and adjusted calcium discrepantPoor correlation between adjusted and

ionised calcium Increased protein (non-albumin) bound

calcium?Pseudohypercalcaemia?Multiple myeloma?ParaproteinaemiaSuggest serum electrophoresisSuggest urine Bence-Jones

protein/electrophoresis Suggest serum free light chainsSuggest immunoglobulins

Normal ionised calciumNormal parathyroid hormone (PTH)HypercalcaemiaIncreased serum total/adjusted calcium?Malignancy Suggest repeat calcium/PTH for

confirmationHypoalbuminaemiaClinical status/back painSuggest full blood countSuggest renal function testsSuggest urine calciumSuggest serum total proteinSuggest electrolytes, urea, creatinineNormocalcaemiaSuggest erythrocyte sedimentation rate?InflammationSuggest bone marrow aspirateSuggest beta-2 microglobulinIf confirmed patient should be referredCheck total calcium with different assay

?HyperparathyroidismSuggest phosphateSuggest vitamin DSuggest alkaline phosphatase (ALP)?Drug/medication induced?Secreting PTH-related peptide?Exogenous vitamin DSuggest liver function testsConsider renal failureSuggest review clinical history/status?Familial hypocalciuric hypercalcaemia?Breast/lung/kidney cancerSuggest magnesium?Increased calcium due to tourniquet time

Suggest bone markers?Liver diseaseSuggest TSHSuggest fasting calcium?Chronic diseaseSuggest urine protein/albuminEuparathyroidismMonitoring of patient calcium level required

Suggest vitamin D supplementationAlbumin should be corrected tooHyperparathyroidism unlikelyExclude recent blood transfusion


Suggest bone scan/CT/imagingSarcoidosis?Hyperthyroidism?Malnutrition?Renal/GIT loss?DehydrationNo abnormalitySuggest repeat in 3 monthsNot clinically significant hypercalcaemiaNot suggestive of malignancyGI loss unlikelySuggest calcitonin

Case 9-04 Urate



Clinical Notes on Request FormCheck-up

Case DetailsSerum Urate 0.48 mmol/L (0.20–0.42)

Suggested CommentMild hyperuricaemia may be associated with renal failure, high purine diet, ethanol, diuretics and increased cell turnover states. Hyperuricaemia is associated with an increased risk of gout. Further investigation/management would be based on context of test request.

Rationale Factors that increase serum urate include renal failure, high purine diet, ethanol, diuretics and increased cell turnover states, as well as rare enzyme defects such as phosphoribosylpyrophosphate (PRPP) synthetase superactivity and hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. A 24-hour urine collection on a standard diet excluding alcohol and drugs known to affect urate metabolism will allow differentiation of overproduction of uric acid versus undersecretion, but this is rarely required in routine practice.

The diagnostic test for gout is the demonstration of urate crystals in joint aspirate. Serum urate is the most important risk factor for gout and reduction of serum urate in this context is beneficial. However, only a small minority of people with hyperuricaemia (defined as serum urate >0.42 mmol/L) will develop gout. About 40% of patients presenting with acute gout have serum urate <0.42 mmol/L, but note that serum urate is a negative acute phase reactant and may decrease during an acute attack. In absolute terms, at any given level of serum urate, the risk of gout is the same for men and women.

Hyperuricaemia is associated with insulin resistance, obesity, hypertension and hypertriglyceridaemia. It has been suggested to be an independent risk factor for cardiovascular disease and for the future development of hypertension and renal disease. However, the role of serum urate as a marker for cardiovascular risk is not established and it is not included in risk calculation. There is no conclusive evidence yet to recommend urate-reducing therapy in this context.

References1. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I:

Diagnosis. Ann Rheum Dis 2006;65:1301-11.2. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in

the Normative Aging Study. Am J Med 1987;82:421-6.3. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenic role for uric acid in hypertension and

cardiovascular and renal disease? Hypertension 2003;41:1183-90.



Mild hyperuricaemia?Asymptomatic hyperuricaemiaHyperuricaemia alone not diagnostic for

gout?Urate underexcretion?Urate overproduction?Renal impairment?Excess alcohol?Diuretics/aspirin/drugs?Increased purine intakeMaintain urate <0.36 mmol/L if on

treatment Suggest full history/clinical examinationSuggest urea/creatinine/electrolytesIncreased risk of goutAssociated/assess metabolic syndromeAssociated/assess cardiovascular diseaseSuggest fasting blood sugar

concentrationsSuggest fasting lipidsSuggest full blood countSuggest liver function testsSuggest tests for secondary diseaseSuggest monitoringRisk of urolithiasis?Obesity?Hypertension?HypothyroidConsider diet/lifestyle changes?Abnormal lipid profileSuggest calcium/phosphate

Hyperuricaemia?Gout?Diabetes?Arthritis?Hyperparathyroidism?Primary or secondary disorderSuggest urate pre/post low purine diet?Prolonged fasting/stress/exerciseNo comment issued routinely?Lead poisoningRisk of gout if urate >0.42 mmol/L?IdiopathicUrate lowering treatment if clinically

indicated?DehydrationTreatment dependent on

overproduction/underexcretionSuggest urine albumin/pH/microscopyUrate levels higher in malesSuggest electrophoresis?Genetic causeUrate antioxidant properties?SarcoidosisRepeat urate with normal diet/exerciseAcute gout not excludedGenetic causes less likely Suggest 24 h urine urate/creatinine?Psoriasis?Malignancy/haematological

disorder/chemotherapy

Repeat urate on fasting sampleConsider diurnal/seasonal variationAdvise urate lowering treatmentRisk of gout if urate >0.32 mmol/L?FastingSuggest HbA1cRisk of gout if urate >0.60 mmol/LLow risk gout at this level?Probable insignificant increase in urateConsistent with goutModerate hyperuricaemiaSuggest rheumatoid factor/anti-nuclear antibodies

?Vitamin B12 deficiency?Hypoparathyroid

Case 7-07 Glucose



Clinical Notes on Request FormCollapsed

Case DetailsPlasma

Sodium 122 mmol/L (134–146)Potassium 3.7 mmol/L (3.4–5.0)Bicarbonate 27 mmol/L (22–32)Urea 7.5 mmol/L (3.0–8.0)Creatinine 99 µmol/L (60–110)Glucose 0.6 mmol/L (3.0–5.4)CK 13,800 U/L (30–190)cTroponin T 0.02 μg/L (see below)

Additional Information<0.03 Myocardial damage unlikely0.03–0.09 May suggest increased cardiac risk in the setting of acute coronary syndrome≥0.10 Consistent with myocardial infarction if associated with ischaemic symptoms or

ECG changes

Suggested CommentProfound hypoglycaemia – suggest check insulin, C-peptide, and possible inappropriate sulphonylurea ingestion. Concomitant hyponatraemia suggests possible adreno-cortical insufficiency. Suggest urine electrolytes, cortisol, thyroid function tests, endocrine review and pituitary investigations as appropriate. Marked CK elevation is of likely skeletal muscle origin, possibly due to seizure or compartment syndrome, although hypothyroidism may be contributory.

Rationale The cause of collapse in this patient is likely due to hypoglycaemia. For investigation of low glucose, other samples should have ideally been taken prior to the result, especially for insulin, C-peptide, drug screen (sulphonylurea and others) and cortisol. Non-suppressed insulin and C-peptide would favour inappropriate sulphonylurea ingestion and be an indication for drug screen. Insulin administration is possible, in which case C-peptide would be suppressed. Combination of hypoglycaemia with hyponatraemia suggests possible adrenocortical insufficiency (1, 2). One should elicit evidence of clinical volume depletion and salt wasting (urine electrolytes). Clinical endocrine review would corroborate clinical features, discern primary from secondary adrenal insufficiency, and determine the need for a synacthen test and pituitary investigations. Low-normal potassium and normal bicarbonate favour secondary adrenal insufficiency. Hypothyroidism may be associated with, and contributory to, hyponatraemia and CK elevation. Elevated CK is disproportionate to the just-detectable troponin and suggests skeletal muscle aetiology, possibly secondary to compartment syndrome (if immobile for a long time), seizure (secondary to hypoglycaemia), or hypothyroidism. If clinical probability of acute coronary syndrome is low, just-detectable troponin should still be regarded as a prognostic factor.

References1. Frost P, Williams AB. A 57 year old woman admitted to the emergency department with

hyponatraemia and hypoglycaemia. Crit Care Resusc 2000;2:308-9.

2. Diederich S, Franzen NF, Bähr V, et al. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur J Endocrinol 2003;148:609-17.



?Exogenous/endogenous insulin?Oral hypoglycaemic agentsSuggest toxicology screenSuggest C-peptide and insulin? Suggest serum and urine sodium and

osmolality?Adrenal insufficiency/failureSuggest cortisol/adrenal studiesSuggest thyroid function tests?HypopituitarismSuggest pituitary test(s)Muscle damage/rhabdomyolysisAt risk of renal failure

HypoglycaemiaElevated CKHyponatraemiaReview medications / drug historySuggest repeat/serial troponin T?Alcohol abuseNon-cardiac causeCardiac injury not excludedImmediate glucose administration

requiredSuggest liver function testsSuggest clinical endocrine review?Seizure activity?HypothyroidismSuggest/monitor electrolytes/glucoseSuggest alcohol level?SIADHMonitor renal function?Malignancy?Liver dysfunctionExcess sodium loss?Inadequate salt intake

History of collapseNon-elevated troponinSuggest myoglobin?ArtefactSuggest CK isoenzymes?Fluid/electrolyte redistribution?Septicaemia/sepsis?Physical activity?Cerebral event?Diabetic coma?Renal disease?Other rare causesSuggest miscellaneous tests?Prolonged hypothermia?Trauma?HyperthermiaNormal potassiumRepeat tests to confirmSuggest muscle autoantibodiesThis troponin level uninterpretableNo renal failure?Congestive cardiac failureAdequate hydration required

Case 8-01 Glucose



Clinical Notes on Request FormPast history of gestational diabetes.

Case Details75 g oral glucose tolerance test

0 min glucose 5.8 mmol/L60 min glucose 13.1 mmol/L120 min glucose 5.6 mmol/L

Additional InformationPrevious fasting glucose 6.1 mmol/L

Suggested CommentNormal glucose tolerance test. Suggest repeat fasting glucose in 12 months’ time.

Rationale The three main questions on this case are the diagnosis, the tool to use for follow-up (fasting glucose or oral glucose tolerance test, OGTT) and the timing of any follow-up. With regard to diagnosis there is difficulty deciding which guidelines to follow. Several professional bodies, including the Royal College of Pathologists of Australasia, the Australasian Association of Clinical Biochemists and World Health Organization define impaired fasting glucose (IFG) as a fasting glucose result in the range 6.1 to 6.9 mmol/L. Since 2003, the American Diabetes Association guidelines have expanded this to 5.6 to 6.9 mmol/L.

Briefly, arguments for the lower cut point include: the higher cut point is associated with lower test sensitivity for diabetes, the narrower biochemical definition of IFG meant poorer test reproducibility (i.e. patients are more likely to be differently classified on different occasions) as the within-individual biological variation for glucose is relatively large, lower IFG cut point may allow more patients with undiagnosed diabetes to be subjected to OGTT, in certain studies using receiver operating curve analyses, lower IFG cut points of 5.2–5.7 mmol/L are optimal for predicting diabetes risk. Conversely, arguments against the lowering of cut point include: marked increase in the prevalence of IFG in adult population (30–40% vs 7–10%), poorer risk prediction for diabetes, poorer risk prediction for all-cause and cardiovascular mortalities and the potentially enormous public health costs to manage the significantly increased number of patients classified as IFG. The excellent point-counterpoint arguments can be found in the references and are highly recommended readings.

With this conflict between guidelines laboratories must choose which is more appropriate for use. The assessment of this case has been made using the local guidelines on the grounds that most clinicians would be more familiar with them. The local guidelines support following up testing with fasting plasma glucose (rather than OGTT) at one year for patients at high risk, which is appropriate as this patient has a recent result indicating IFG as well as a history of gestational diabetes.

References 1. Shaw JE, Zimmet PZ, Alberti KG. Point: impaired fasting glucose: The case for the new American

Diabetes Association criterion. Diabetes Care 2006;29:1170-2.2. Dekker JM, Balkau B. Counterpoint: impaired fasting glucose: The case against the new American

Diabetes Association guidelines. Diabetes Care 2006;29:1173-5.



Normal glucose toleranceNormal fasting blood glucose Not diabeticPrevious impaired fasting glucose results

increase riskHistory of gestational diabetes increases

riskRetest glucose at 1 year

Impaired fasting glycaemiaSuggest repeat OGTT 1–2 yearsMeasure glucose (other than at 1 year)Fasting blood glucose results increase

riskHigh 1h glucoseNormal 2h glucoseMonitor patientLifestyle modification suggestedClinical evaluation/history requiredPrevious impaired fasting glycaemia1h glucose result increases riskElevated fasting blood glucoseSuggest renal function testsIndeterminate resultsRepeat OGTT <12 monthsSuggest assess cardiovascular risk factors1h glucose not interpretableDiabetes unlikely?Rapid gastric emptying?Hyperthyroidism?Abnormal glucose metabolismEarly glucose intoleranceSuggest lipidsEquivocal fasting blood glucose?Patient fasted correctlyConsider insulin resistanceAdequate glucose absorption

Impaired glucose toleranceSuggest HbA1c1h glucose indicates diabetesSuggest insulin measurementSuggest repeat OGTT 3 yearsSuggest thyroid function tests for ?hyperthyroidism

Case 9-03 Glucose



Clinical Notes on Request FormDizziness, sweating and confusion. Not on any medication.

Case DetailsSerum glucose 2.5 mmol/L (3.0–5.4)

Additional InformationSodium 141 mmol/L (134–146)Potassium 4.0 mmol/L (3.4–5.0)Bicarbonate 27 mmol/L (22–32)Urea 5.2 mmol/L (3.0–8.0)Creatinine 72 μmol/L (60–110)eGFR >60 mL/min/1.73m2 (>60)Total protein 83 g/L (60–80)Albumin 48 g/L (35–50)Calcium 2.35 mmol/L (2.15–2.60)Bilirubin 10 μmol/L (<20)Alk. Phos. 63 U/L (35–135)ALT 44 U/L (< 40)Gamma GT 38 U/L (< 60)

Suggested CommentThe symptoms are consistent with the neurological manifestation of hypoglycaemia (neuroglycopaenia), which is supported by the low serum glucose. Adult hypoglycaemia presentations to emergency departments are most commonly due to complications of diabetes therapy or alcohol abuse. If aetiology is uncertain, useful tests may include insulin, C-peptide, cortisol and sulphonylurea screen. The latter three may be added to the original sample, if sufficient volume remains.

Rationale The presenting symptoms and low serum glucose in this case are consistent with the neuroglycopaenia. An important confirmatory factor is the resolution of the symptoms with administration of glucose (Whipple’s triad). Once confirmed, investigation of the hypoglycaemia will depend on the history and relative likelihood of possible causes. In the Emergency Department, diabetes therapy (most importantly, insulin and sulphonylurea) and alcohol account for the majority of hypoglycaemia presentations. However, the history in this case indicates no medications.

Renal and hepatic failures can cause hypoglycaemia, and are excluded by the normal renal and liver function tests. Other causes include adrenal failure, insulin-secreting tumour and factitious hypoglycaemia, which are relatively rare but may also be important. The choice of tests will be directed by the clinical picture. Another important consideration is the need to obtain appropriate samples at the time of a hypoglycaemic episode for some tests. It may be useful to take this opportunity to investigate this case further, especially if there have been previous episodes. Insulin, C-peptide, cortisol and sulphonylurea screen may be the best first-line tests during an episode, with additional testing later if indicated. Note that sulphonylurea screens are performed on serum and not urine samples.



Symptomatic hypoglycaemiaMarked hypoglycaemia ?Hypoglycaemic agentsIatrogenic causes most common?Drug-induced?Exogenous insulin?Insulinoma?Adrenal insufficiency Test during hypoglycaemic episodeSuggest insulinSuggest C-peptide?AlcoholSuggest insulin if clinically indicatedSuggest C-peptide if clinically indicatedSuggest sulphonylurea screen if clinically

indicatedSuggest sulphonylurea screenSuggest cortisolSuggest pituitary and adrenal testsSuggest further investigation

HypoglycaemiaSuggest repeat glucose?Reactive hypoglycaemia?Fasting or postprandial glucose?Early diabetesOther biochemistry normal?Endocrine disorderHistory of no medications notedRequest detailed history?Prolonged fastingSuggest glucose replacementSuggest OGTT (extended) if clinically

indicatedSuggest investigate with prolonged fastMarginally elevated ALT/total protein?Functional hypoglycaemiaFluoride oxalate collectionSuggest OGTTExclude artefactual causesSuggest growth hormone?Factitious hypoglycaemia?Symptom recovery with normal blood

sugar levelSuggest drug screenSuggest TSHSuggest ACTHInvestigate diet?Post-gastrectomy?Pancreatic tumour?Extrapancreatic tumoursArtefact unlikelyConsider imagingInsulinomas are rareSuggest insulin antibodies?SepticaemiaDifferentiate endogenous vs exogenous

insulinSuggest IGF/IGFII/IGFBP3No investigation if single episode?Diarrhoea/vomiting?Islet cell hyperplasia?Overdose hypoglycaemics/ ?non-

compliant?Immune hypoglycaemiaHypoglycaemia 2° to liver disease

unlikelySuggest short synacthen if clinically

indicatedSpecialist opinion may be requiredSuggest investigate with 24 h fast?Endocrine neoplasmsPituitary and adrenal disease less likely

Suggest urine hypoglycaemic agent screen

?Galactosaemia?Glycogen storage disease?DehydrationSuggest hepatitis serologySuggest catecholaminesInsulinoma is a common cause?Liver/renal failureSuggest glucagon measurement?Leucine/fructoseSuggest DHEASSuggest proinsulinSuggest electrolytesNilSuggest ketonesMild hypoglycaemiaSuggest lactateInsulin overdose excluded

Case 10-09 Glucose

Patient ID 2-year-old boy


Clinical Notes on Request FormHistory of convulsions soon after awakening

Case DetailsResults from the Emergency Department

Plasma glucose 1.7 mmol/L (Fasting: 3.5–5.5)Urine ketones 4+Calcium 3.37 mmol/L

Suggested CommentThese results are consistent with a diagnosis of idiopathic ketotic hypoglycaemia. Other endocrine, metabolic and toxicological causes should be excluded with tests collected whilst the patient is hypoglycaemic. These should include electrolytes, creatinine and liver function tests, cortisol, growth hormone, insulin, lactate, beta-hydroxybutyrate, free fatty acids, blood gases, ammonia, organic acids and acylcarnitines. The raised ketones make insulin excess and fatty acid oxidation defects less likely.

Rationale Idiopathic ketotic hypoglycaemia (IKH) is a condition characterised by fasting hypoglycaemia and increased concentrations of ketones. By contrast, ketones are usually low in children with fatty acid oxidation defects or those who have insulin-secreting tumours or those who have ingested sulphonylureas. IKH is the most likely cause of the findings in this case, although careful history and testing are needed to exclude other causes. IKH usually occurs after 12 months of age and resolves over several years.

In a recent case series, IKH is the most common cause of hypoglycaemia in previously healthy children presenting to the Emergency Department. They usually first present before the age of 5 years with symptomatic hypoglycaemia, which resolves after administration of glucose, and ketonuria during the morning hours after a moderate fast. They are more likely to be Caucasian, male gender, and have a low body weight.

The underlying pathophysiology of IKH is yet to be fully understood. It is often associated with low plasma concentrations of alanine, an important substrate for gluconeogenesis, and may involve impaired ketone body metabolism or transport. It is sometimes called ‘accelerated starvation’ and is more common in babies that were small for dates and had neonatal hypoglycaemia.

References1. Daly LP, Osterhoudt KC, Weinzimer SA. Presenting features of idiopathic ketotic hypoglycemia. J

Emerg Med 2003;25:39-43.2. Marcus C, Alkén J, Eriksson J, et al. Insufficient ketone body use is the cause of ketotic

hypoglycemia in one of a pair of homozygotic twins. J Clin Endocrinol Metab 2007;92:4080-4.



Idiopathic ketotic hypoglycaemiaKetotic hypoglycaemiaExclude inborn errors of metabolism?Drug ingestion ?medications ?

overdose ?reaction?Adrenal insufficiency ?Addison’s?Hypopituitarism?Hypocortisolism Ketosis, fatty acid oxidation disorders

less likelyCollect samples when hypoglycaemicSuggest insulin/C-peptideSuggest cortisol/ACTHSuggest growth hormoneSuggest lactateSuggest urine/plasma organic acidsSuggest free fatty acids - exclude fatty

acid oxidation disordersSuggest amino acid screenSuggest carnitine/acylcarnitine screenSuggest electrolytes/renal function

tests/liver function tests/glucose/Ca/Mg Suggest β-hydroxybutyrate/urine ketonesSuggest blood gas/pHSuggest urine metabolic screenSuggest ammonia?Growth hormone deficiencySuggest urine amino acidsUrgent oral/IV glucose/admit hospitalRepeat glucose regularly

Marked hypoglycaemiaKetosis/ketonuriaExclude endogenous/exogenous insulin

excess?Malnutrition ?starvation ?long fastHypoglycaemiaSuggest thyroid function tests?Glycogen storage disease?Salicylate/paracetamol/alcohol overdoseRefer to endocrinologist/specialist?Gluconeogenic defect?Organic acidaemia?Liver disease ?hepatic enzyme defectSuggest supervised diagnostic fast?Sepsis – complete blood

picture/blood/urine culturesKetosis - hyperinsulinaemia less likelyExclude MCAD?Family historyKetosis excludes hyperinsulinaemiaAssume correct specimen collectionReview original Guthrie screenExclude respiratory chain disorders?Galactosaemia?Fructose intolerance?Leucine sensitivity?Reye’s syndrome

?Intercurrent illness?Hormone deficiency?Insulin dependent diabetes mellitusSuggest urine reducing substancesConvulsion from hypoglycaemia?Pyruvate metabolism disorderSuggest IGF-1?Tissue biopsy for inborn errors of metabolism investigation

Suggest glucagonSuggest HbA1cSuggest urine microalbumin?Adrenoleukodystrophy or congenital adrenal hyperplasia

Suggest 17OHPSuggest genetic test if amino acid positive

Suggest G6PDRisk of mental retardation/seizures?Low weight for height?Abdominal mass?NeoplasmKetosis excludes fatty acid oxidation disorders

Case 11-10 Glucose



Clinical Notes on Request Form28/40 pregnant.OGTT (75 g oral glucose load)

Case DetailsFasting glucose 5.1 mmol/L1 h glucose 10.3 mmol/L2 h glucose 5.3 mmol/L

Suggested CommentThe latest Australian Diabetes in Pregnancy Society definitions for gestational diabetes (GD) using 75 g oral glucose tolerance test (OGTT) are: fasting glucose <5.1 mmol/L, 1 hour <10.0 mmol/L and 2 hour <8.5 mmol/L. Under these guidelines, this patient should be managed as for GD, including an OGTT 6–8 weeks post-partum.

Rationale Previously, the lack of international consensus on the diagnosis of gestational diabetes (GD) makes it difficult to be sure what criteria to apply. In 1998 the Australian Diabetes in Pregnancy Society re-affirmed 1991 recommendations of the Australian Diabetes Society to define GD as a fasting blood sugar level (BSL) of ≥5.5 mmol/L or 2 hour post 75 g load BSL of ≥8.0 mmol/L; the 2 hour threshold was derived by rounding the WHO level of 7.8. In 1992 the New Zealand Society for the Study of Diabetes raised the 2 hour threshold to 9.0 mmol/L for New Zealand. The American Diabetes Association favours the 3 hour 100 g OGTT but also use two abnormal readings [≥5.3 mmol/L (fasting), ≥10.0 mmol/L (1 hour) and ≥8.6 mmol/L (2 hour)] post 75 g load.

After publication of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, which conclusively links multiple adverse pregnancy outcomes with degrees of hyperglycaemia less severe than those diagnostic of diabetes, the International Association of Diabetes and Pregnancy Study Groups recommended a uniform approach to GD diagnosis.

The proposal includes: 1. Use of random/fasting BSL or HbA1c in 1st trimester to exclude undiagnosed overt diabetes. 2. Diagnosis of GD based on either BSL ≥5.1 mmol/L (fasting), 10.0 mmol/L (1 hour) or 8.5 mmol/L (2 hour) post 75 g load at 24–28 weeks.

These figures represent the average BSL exceeded in HAPO where the odds ratio for adverse outcomes reached 1.75. While not directly addressed, the non-fasting ‘screening’ test will be redundant. These criteria are now adopted by the Australian Diabetes in Pregnancy Society and World Health Organisation.

Reference1. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, et al.

International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676-82.



Raised 1h resultGestational diabetes by IADPSG criteriaGestational diabetesSuggest manage patient as gestational

diabetes mellitusPregnancy OGTT guidelines differContinue to monitor post-partumRepeat OGTT post-partum75 g glucose load

Repeat GTT if clinically indicatedGlucose tolerance can deteriorate in later pregnancySuggest further tests if risk factorsCheck specimen integrity and orderGuidelines suggest fasting plasma glucose, HbA1c 1st trimesterIncreased risk of diabetes mellitusInterpret with caution during pregnancyReview of gestational diabetes mellitus criteria from HAPO?Patient fastingCheck pre-test conditions1h suggests normal absorption of glucoseRepeat GTT 3rd trimester if clinically indicatedIf non-fasting, positive 1h resultRaised 1h result ?rapid absorptionConfirm gestational diabetes mellitus diagnosis

Suggest polycose screen (GCT)Gestational diabetes mellitus indicated by ADA criteria

GTT protocol not followedGestational diabetes mellitus using ADIPS 1998

Normal GTTNormal GTT using ADIPS criteriaNot suggestive of gestational diabetes

mellitusNormal GTT using WHO criteriaNo gestational diabetes mellitus using ADA 1999

Case 12-07 Glucose



Clinical Notes on Request FormDiabetes monitoring

Case DetailsHbA1c 6.8%HbA1c (IFCC) 51 mmol/mol

Additional InformationType 2 diabetes for 5 years. On metformin.

Suggested CommentAs the general target for HbA1c in a patient with type 2 diabetes for 5 years on metformin therapy alone is 6.0% (42 mmol/mol), the management of this patient should be reviewed. If the patient has clinical cardiovascular disease a higher target may be appropriate.

Rationale The Australian Diabetes Society has produced guidelines for the individualisation of HbA1c targets based on a range of factors (1, 2). Factors to consider with these individualised targets include the type of diabetes (type I or type II), the duration of diabetes, treatment, presence of cardiovascular disease, pregnancy, recurrent hypoglycaemia and hypoglycaemia unawareness.

In the supplied case, a number of these factors were specified (type II diabetes mellitus, duration five years, metformin only) for which the target HbA1c is <6.0% (<42 mmol/mol). A higher value may be appropriate in this patient if there is clinical cardiovascular disease. It is difficult for the laboratory to be aware of all these factors when issuing an interpretive comment, but care should be taken not to place a comment which conflicts with these guidelines. Participants in countries other than Australia should refer to relevant guidelines in their own country.

Responses suggesting a specific course of action were generally marked as ‘Less Relevant’. From the laboratory, it is not possible to determine whether changes in lifestyle, metformin dose or drug treatment is the preferred option.

References1. Cheung NW, Conn JJ, d’Emden MC, et al. Position statement of the Australian Diabetes Society:

individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191:339-44.

2. Jones GR, Barker G, Goodall I, et al. Change of HbA1c reporting to the new SI units. Med J Aust 2011;195:45-6.



Results above limits 6% or 42 mmol/molShort term diabetes mellitus without

cardiovascular disease target <6%, 42 mmol/mol

Short term DM without CVD target 6–6.5%

HbA1c target 6–6.5% (45–49 mmol/mol)If cardiac risk target <6.5%If long-term or cardiovascular disease,

target <7%, 53 mmol/molTargets should be individualised Need to lower HbA1c levelsRecommend lifestyle changes ±

metformin target <6%Suggest repeat HbA1c in three monthsRefer Aust. Diabetes Society guidelinesRefer Med J Aust 2011 position

statementRefer Med J Aust 2009 position

statementRefer NZ guidelines Type 2 DM (2011)

HbA1c general target <7% or 53 mmol/mol

Check lipids, urine albumin/creatinine, renal function

Dual reporting of unitsCheck other cardiovascular risk factorsRecommend annual urine

albumin/creatinine, lipidsEarly control lowers microvascular/

macrovascular complicationsADA, BPAC NZDA, IDF target 6.5%Recommend lifestyle changesHbA1c 5–6% reduces cardiovascular

disease?Variant Hb produce artefacts?ComplianceRepeat HbA1c in six monthsConsider hypoglycaemic episodes?Modify metformin doseRecommend lifestyle changes (<6% or

<42 mmol/mol)?Lower target with new diabetics?Consider lower target no cardiovascular

diseaseReporting IFCC unitsUKPDS early treatment of DM beneficialCheck fasting glucoseHbA1c <1% above reference limit 4–6%Suggest microalbuminCheck for hypertension?Suggest sulfonylurea or insulinNot using IFCC unitsCare required when interpret increased

red blood turnoverConsider patient symptoms?Medication to reduce symptomsPatient risk of retinopathyConsider oral anti-diabetic therapyFollow-up 3–6 monthsRefer Clin Chem guidelines 2011Review of diabetes management

suggested if HbA1c =>7.0%Target for type 2 DM 50–55 mmol/molFor younger people tighter control

required

Good glycaemic controlPoor diabetic controlTargets balanced against risk of hypoglycaemia

?Risk hypoglycaemia 2° to treatmentChange treatment if >8.0% (64 mmol/mol)

Should achieve <6% accord to UKPDS


Very good glycaemic controlNo change medication/dosage require

Case 14-01 Glucose



Clinical Notes on Request FormPrevious impaired fasting plasma glucose (FPG). Normal body mass index (BMI) and no family history of diabetes mellitus.

Case DetailsHbA1c (IFCC) 48 mmol/molFasting plasma glucose 6.4 mmol/L

Additional InformationPrevious FPG as part of a screening for being a possible live kidney donor showed a FPG of 6.1 mmol/L. This was followed up by an HbA1c and an oral glucose tolerance test (OGTT):HbA1c (IFCC) 46 mmol/molOGTT 0 hour glucose 5.2 mmol/L

2 hour glucose 5.5 mmol/LAll haematology was normal.

Suggested Comment(Australia) Single HbA1c result above the diagnostic threshold for diabetes mellitus together with a fasting blood glucose in the range for impaired fasting glucose. A repeat HbA1c test in 3 months is recommended for confirmation of diagnosis of diabetes. (New Zealand) HbA1c result in the pre-diabetic range. Repeat testing in 6–12 months is recommended to assess progression.

Rationale HbA1c is now approved for the diagnosis of diabetes mellitus (DM) in Australia (1) and New Zealand (2), providing it is measured in an accredited laboratory using a National Glycohemoglobin Standardization Program (NGSP)-certified method. Briefly, in Australia, the WHO criterion (3) of two results ≥48 mmol/mol (6.5%) in an asymptomatic patient has been adopted. In New Zealand the criterion is two results ≥50 mmol/mol (6.7%) for asymptomatic patients. Either venous plasma glucose or HbA1c are valid for the diagnosis of DM and if either testing protocol is positive the diagnosis is made. It is not recommended that both glucose and HbA1c testing protocols be used in the same patient at the same time. Doctors may choose HbA1c to test patients who are not fasting.

HbA1c should not be used in patients with factors that make testing unreliable including iron deficiency, stage 4 or 5 chronic kidney diseases, haemolytic anaemia or other cause of reduced red blood cell survival and haemoglobinopathies that affect the laboratory method in use. HbA1c should not be used for diagnosis of acute onset DM (e.g. Type 1) or for gestational DM. While HbA1c is a valid test for diabetes in Australia, details on recommended testing protocols (e.g. retesting frequency) are still under development. In contrast, in New Zealand HbA1c is recommended as the preferred test unless there are specific contraindications.

In this case, where results are available for fasting plasma glucose, oral glucose tolerance test and HbA1c, unless there are specific contraindications it would seem that HbA1c is likely to be the more sensitive test for diagnosis and should be used for further assessment.

References1. d'Emden MC, Shaw JE, Colman PG, et al. The role of HbA1c in the diagnosis of diabetes mellitus in

Australia. Med J Aust 2012;197:220-1.

2. Braatvedt GD, Cundy T, Crooke M, et al. Understanding the new HbA1c units for the diagnosis of Type 2 diabetes. NZ Med J 2012;125:70-80.

3. World Health Organization. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. 2011. http://www.who.int/diabetes/publications/report-hba1c_2011.pdf



Borderline HbA1cNot diagnostic of diabetes(Aus) DM cut-off HbA1c ≥48 mmol/molOral glucose tolerance test (OGTT) and

HbA1c discordantNZSSD position statement prediabeticConsistent with pre-diabetesFasting plasma glucose (FPG) consistent

with impaired fasting glucoseHbA1c above diabetes mellitus (DM)

cut-offHigh risk of developing diabetesRecommend lifestyle reviewRecommend cardiovascular disease risk

assessmentUse repeat HbA1c to confirm DMRepeat screening HbA1c in futureSuggest lipid profileConfirm DM if asymptomaticRe-screen DM in future OGTT or HbA1c results diagnose DM HbA1c - WHO criteria for Type II DMAssuming valid HbA1c

Normal OGTTClinical/previous history notedRe-screen in future with OGTTRe-screen in future with FPGAustralian guidelines confirm DMFPG and HbA1c discordant still

diagnosticHbA1c not funded for diagnosis of DMCheck urine albumin/creatinine ratio?Technical problem with OGTTSuggest fasting glucoseAustralian Diabetes Society HbA1c

targets for diabeticsImpaired fasting glucose consistent with

insulin resistanceHbA1c better diagnostic toolConfirm DM with OGTT

Impaired glucose toleranceHbA1c - impaired glucose toleranceHbA1c not supported in Australia for diagnosis


Normal HbA1c levelRepeat HbA1c to monitor DM

http://www.who.int/diabetes/publications/report-hba1c_2011.pdf

Case 6-09 Liver



Clinical Notes on Request FormAcutely ill with nausea and vomiting

Case DetailsPlasma Liver Function Tests

Albumin 28 g/L (35–50)Bilirubin 61 µmol/L (<20)ALT 2627 U/L (<46)AST 2196 U/L (<33)Alk Phos 69 U/L (35–135)Gamma GT 198 U/L (<44)

Additional InformationOther laboratory results: Urea and electrolytes unremarkable

Suggested CommentResults indicate acute hepatitis. Consider viral hepatitis serology, possible adverse drug reactions, and exclude paracetamol or other toxic substances.

Rationale It is a good general rule to go for the obvious and gross when looking at results. In this case the transaminases are very high indicating acute hepatitis, and other minor abnormalities are likely to be secondary to this.

The causes of ALT >1000 are few - viral hepatitis, toxins such as paracetamol, adverse drug reactions, ischaemic hepatitis secondary to hypotension, and ante-mortem with severe heat stroke. In a man of this age and with the history given, the latter two can probably be ruled out. In this patient, viral hepatitis and adverse drug reactions of one sort or another are highly likely. Of note, an early and rapid rise of LDH, AST:LDH ratio of <1.5 and rapid fall in AST after the initial rise are features suggestive of ischaemic liver injury rather than viral hepatitis.

Remember that drug screens and paracetamol concentration may be difficult to interpret, as it may be some time since ingestion and the drug may be nearly absent or at low concentration.



Acute hepatitisHepatocellular pathology?Drugs/chemicals?Viral infectionSuggest viral serologySuggest paracetamol levels

Acute insultElevated AST/ALT?Ethanol?HistoryIncreased GGT/bilirubinAbnormal liver function testsSuggest INR/clotting studies?Other causesMild jaundiceSuggest ethanol level?Autoimmune diseaseSuggestive of hepatitis ASuggest toxicology screenNo obstructionAST/ALT indicate non-alcoholicSuggest glucoseHospitalisation/management

recommended

Acute biliary obstruction?Hypoxic insultSuggest other testsSuggest radiographySuggest serial liver function testsSuggest lipase/amylase?Haemolysis?Gilberts?Hepatic failure?Extensive trauma?CholecystitisViral hepatitis unlikelyScreen contacts

Case 7-02 Liver



Clinical Notes on Request FormHistory of gout. Family history of Type II diabetes and cardiovascular disease.

Case DetailsTotal protein 70 g/L (60–80)Albumin 44 g/L (35–50)Bilirubin 11 µmol/L (<20)ALT 48 U/L (<40)AST 22 U/L (<43)ALP 89 U/L (35–135)GGT 79 U/L (<60)

Additional InformationSodium 143 mmol/L (134–146)Potassium 4.2 mmol/L (3.4–5.0)Urea 4.2 mmol/L (3.0–8.0)Creatinine 80 µmol/L (50–110)Glucose 5.8 mmol/L (3.0–5.4)Urate 0.66 mmol/L (0.12–0.45)Cholesterol 7.9 mmol/L (<5.5)Triglyceride 4.5 mmol/L (<2.01)

Suggested CommentMild elevations of ALT and GGT in the setting of mixed hyperlipidaemia and impaired fasting glycaemia suggest possible fatty liver disease. Alcohol and drugs should be considered as possible contributory factors. If history is supportive, hepatitis serology may be indicated.

Rationale Non-alcoholic fatty liver disease (NAFLD) should be considered in patients with asymptomatic elevated aminotransaminases. Liver enzyme elevations are absent in 78% of NAFLD patients, and when present are modest, with AST:ALT ratio <1. GGT when raised is less than in alcohol-induced liver injury. The diagnosis of NAFLD requires 1) imaging or histologic evidence of fatty infiltration of the liver, 2) the absence of excessive alcohol ingestion (men: <21 drinks/week; women <14 drinks/week), 3) no competing aetiologies for hepatic steatosis, and 4) no co-existing cause of chronic liver disease. Obesity, type 2 diabetes mellitus, hypertension, hypertriglyceridaemia, low HDL-cholesterol and metabolic syndrome are risk factors associated with NAFLD. Competing causes of hepatic steatosis, such as hepatitis C, medications, parenteral nutrition, Wilson’s disease, severe malnutrition as well as other causes of chronic liver disease should be excluded by clinical evaluation and serological testing. Confirmation of diagnosis is by imaging studies, although liver biopsy should be considered in patients with metabolic syndrome, high NAFLD Fibrosis Score, and in whom competing aetiologies or chronic liver disease cannot be excluded without a biopsy.

Reference1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty

liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-23.



Mild liver enzyme abnormalities?Alcohol and/or drugs?Fatty liver disease?Metabolic syndromeSuggest hepatitis serology

HyperuricaemiaHyperlipidaemiaRecommend oral glucose tolerance testRecommend repeat fasting lipids & HDLHyperglycaemiaConsistent with gout?FastingSuggest repeat fasting glucoseSuggest lifestyle changes?Viral hepatitisSuggest repeat tests laterSuggest further liver investigation?Hepatocellular injurySuggest clinical reviewAt cardiovascular risk?ObesitySuggest urinalysis/ urine microalbumin?Insulin resistanceReview cardiac risk factorsRecommend HbA1cSuggest other testsNormal renal function testsSuggest insulin levelsSuggest further lipid testsRecommend liver imaging

?Diabetes mellitusSuggest statin/pharmacotherapySuggest thyroid function testsFamilial hypercholesterolaemia?Increased cell turnover/malignancy?PancreatitisHepatic impairment No comment

Case 9-06 Liver



Clinical Notes on Request Form135 kg, bipolar on Epilim (sodium valproate) 2 x 200 mg BD

Case DetailsBilirubin 12 µmol/L (3–20)ALP 81 U/L (30–115)AST 193 U/L (5–40)ALT 124 U/L (5–40)GGT 21 U/L (5–65)LD 238 U/L (100–225)

Additional InformationEpilim 22 mg/L (50–100)

Suggested CommentHepatocellular dysfunction may be related to valproate toxicity even though the valproate concentration is below the usual therapeutic range. Other causes of liver disease should be investigated. The disproportionate increase in AST compared with ALT may be seen in ethanol-associated liver disease or with concurrent muscle injury. Measurement of serum CK may be helpful.

Rationale Initial and chronic ingestion of valproate may cause dose-dependent, reversible minor elevation of hepatic transaminases. On the other hand, valproate can cause fatal idiosyncratic hepatotoxic reactions. Anyone can be affected but children under 2 years old with organic brain disease, congenital metabolic disorders, developmental delay and taking multiple medications may be at increased risk. The idiosyncratic hepatotoxicity may not be related to increased serum valproate concentration. Therapeutic drug monitoring of valproate is less useful than other anticonvulsants like phenytoin because of a weaker correlation between serum concentrations and therapeutic effect or toxicity.

Reference 1. Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig

Liver Dis 2006;38:33-8.



Consistent with hepatocellular damageEpilim hepatotoxicitySub-therapeutic Epilim levelExclude other causes of liver diseaseAssess patient clinically?Alcohol?Muscle involvementSuggest CK/CK-MBEpilim may cause acute liver failureReview pre-Epilim liver function tests

Raised liver transaminases notedMonitor liver function tests?Concurrent drug therapy?Viral hepatitis?Non-alcoholic fatty liver diseaseReview Epilim doseObesity notedSuggest PT/fibrinogen levelsSlightly raised LDH?Non-complianceNormal GGT/ALP/TBilSuggest hepatitis serology?TransientSuggest albumin /total proteinAST>ALT?Recent commencementClinical symptoms better than Epilim

levelConsider alternative drug for bipolar disorder

If no other cause stop EpilimRestrict salicylate/same metabolic path?Hepatocellular disease?Manic episodes or fittingDetails of last dose not stated?Autoimmune disorder?CirrhosisMonitor Epilim levelsSuggest ammonia ?hepatic

encephalopathyValproate highly protein bound?Cardiac involvementEpilim doses lower in bipolar disorderSuggest renal function testsEpilim can cause obesitySuggest fasting glucose/lipids?Risk of pancreatitisAST from other tissues?Liver disease with haematologic

disturbanceSuggest urine myoglobin?Neurometabolic diseaseSuggest liver ultrasoundIn liver disease ALT>ASTSuggest full blood examinationNo commentSuggest troponin T, CK and BNP?Early hepatic failureSuggest free valproic assay?Acute episodeNo evidence of cholestasisIn non-alcoholic fatty liver disease,

AST<ALT?Urea cycle disorder

Not likely hepatic dysfunction due to Epilim

?2° to metabolic syndrome?Renal damageNo evidence hepatotoxicitySuggest hormone levelsSuggest thyroid function tests?End-stage AIDSSuggest C-Peptide Deaths seen in patients on Epilim

Case 9-10 Liver

Patient ID 23-day-old baby

Patient Location Paediatric Ward

Clinical Notes on Request FormIncreasing jaundice.

Case DetailsBilirubin 367 μmol/LConjugated bilirubin 10 μmol/L

Suggested CommentProlonged, marked, unconjugated hyperbilirubinaemia. Breast milk jaundice may be considered after excluding hypothyroidism, sepsis and haemolytic disorders. Suggest thyroid function tests, full blood examination with blood film, direct Coomb’s test, blood group subtyping of mother and baby, glucose-6-phosphate dehydrogenase (G6PD) screen, and urine culture. Clinical advice regarding management is recommended.

Rationale Hyperbilirubinaemia beyond two weeks of age (three weeks if premature) is considered ‘prolonged’. The exclusion of conjugated hyperbilirubinaemia is important, as they are always pathological, requiring urgent attention. Unconjugated hyperbilirubinaemia is most commonly due to breast-feeding but this cannot be assumed without excluding hypothyroidism, haemolysis (from red blood cell abnormalities and atypically late presentations of blood group incompatibility) and infection. It is also important to ensure that routine metabolic screening (including congenital hypothyroidism screening) has been performed. At this level of bilirubin, treatment advice should be sought. It is worthwhile for laboratories to be familiar with local paediatric hospital guidelines, which usually have treatment thresholds relating the levels of bilirubin with the baby’s age and clinical state.

References1. Evans N. Neonatal jaundice. Australian Doctor 2008;8th Feb:21-28.2. NICE clinical guideline 98: Neonatal jaundice. http://www.nice.org.uk/guidance/cg98

http://www.nice.org.uk/guidance/cg98



Unconjugated hyperbilirubinaemiaMarked hyperbilirubinaemiaProlonged hyperbilirubinaemia/jaundice?Breast milk jaundice?Sepsis?G6PD deficiency/other red cell enzyme

defect?Haemolytic condition?HypothyroidismReview clinical picture/historySuggest full blood examinationSuggest thyroid function testsSuggest haemolytic screenSuggest blood group and rhesus and

antibody status of mother and babySuggest sepsis investigationsSuggest red cell G6PD assaySuggest blood filmCheck newborn screening doneSuggest urine microscopy, culture and

sensitivity

?Crigler-NajjarSuggest liver function tests?Pathological impaired liver conjugationRisk of kernicterusSuggest further investigation?Baby premature?GalactosaemiaSuggest reducing substancesMonitorConsider phototherapy?Gilbert’s syndromeHyperbilirubinaemiaOutside timeframe for physiological

jaundiceSuggest TORCH(S) screen?Inborn error of metabolism?Congenital infection?Hereditary red cell membrane defectRefer to paediatrician?Inadequate caloric intakeCease breastfeed to assessNo commentConsider treatment?Thalassaemia/haemoglobinopathy?Prolonged physiological jaundiceTreat to reduce bilirubin if increase

continues?Drug effectSuggest hepatitis screenRepeat total and direct bilirubin in one

day?Excessive red blood cell turnoverSuggest glucoseSuggest C-reactive protein?Lucy Driscoll syndrome?Secondary to acute illnessSuggest serum albumin

Immediate treatment requiredConsider exchange transfusion?Obstructive liver diseaseNo intervention necessaryBilirubin level excludes Gilbert’s Bilirubin level excludes haemolytic disorder

?Hypopituitarism?Hypoxia

Case 10-04 Liver



Clinical Notes on Request FormDecreased conscious state.

Case DetailsPlasma ammonia 375 μmol/L (10–50)

Additional InformationNa 142 mmol/L (134–146) cTnI 0.04 μg/L (<0.04)K 3.8 mmol/L (3.4–5.0) Bicarb. 23 mmol/L (22–32) ABGUrea 6.4 mmol/L (3.0–8.0) pH 7.47 (7.35–7.45)S. Creat. 110 μmol/L (60–110) pCO2 31 mmHg (35–45)eGFR >60 mL/min/1.73m2 (>60) pO2 97 mmHg (80–100)Glucose 6.9 mmol/L (3.0–5.4) O2 sat. 98 % (>95)Protein 67 g/L (65–85) Lactate 1.8 mmol/L (<1.3)Albumin 30 g/L (34–47)T. Bilirubin 26 μmol/L (<22)ALP 106 U/L (30–120)GGT 147 U/L (10–71)ALT 12 U/L (5–40)Lipase 27 IU/L (13–60)

Suggested CommentMarked hyperammonaemia is most likely the cause of the decreased conscious state and respiratory alkalosis. Further investigation for liver and non-liver causes of ammonia toxicity such as drugs (valproate), infective agents, or urea cycle defects is recommended. Suggest hepatitis screen, INR, sepsis screen, urine organic acids, orotic acid and plasma and urine amino acids.

Rationale Mild hyperammonaemia is frequently caused by poor specimen integrity and/or collection technique. Marked hyperammonaemia in the clinical setting of decreased conscious state and respiratory alkalosis makes a spurious result unlikely. Such high ammonia values are most frequently seen in patients with liver failure. The relatively preserved albumin, mildly raised bilirubin and mildly abnormal liver function tests are not consistent with end stage liver failure, as synthetic capacity seems to be at least partly preserved. An INR will be helpful to confirm this.

Non-liver causes of hyperammonaemia, many of which are reversible, should be investigated. Urea cycle (e.g. ornithine transcarbamylase deficiency), fatty and organic acid defects need to be considered as they may present at any age. Valproate can cause hyperammonaemia by N-acetyl-glutamate depletion; although valproate and liver function tests are usually within therapeutic/reference limits. Excessive amino acid load (e.g. gastrointestinal bleeding; unlikely here given the normal urea concentration) and haematologic malignancies are other possibilities. The mildly raised troponin in this setting is difficult to interpret and might be due to a cardiac condition (e.g. cardiac failure) or severe illness (e.g. sepsis). In this particular patient the final explanation was severe right heart failure impeding the ability of the liver to metabolise ammonia loads caused by increased protein intake.

Reference1. Walker V. Severe hyperammonaemia in adults not explained by liver disease. Ann Clin Biochem

2012;49:214-28.



?Chronic hepatic diseaseMarked hyperammonaemiaRespiratory alkalosisCompensated respiratory alkalosisHyperammonaemia coupled with loss of

consciousness?Hepatic encephalopathySuggest further investigation of

hyperammonaemia ?Drug/toxin effect?Sepsis?Valproate aetiology?Urea cycle metabolic defect?Inborn error of metabolismLate onset ornithine transcarbamylase

deficiencySuggest plasma/urine amino acidsSuggest urine organic acids?Hepatotoxicity/acute hepatic injurySuggest clotting profileSuggest plasma acylcarnitineSuggest valproate level?Hyperalimentation

Hyperammonaemia?Ethanol toxicity/alcoholic liver diseaseElevated GGT?Sample integrity/preanalytical

interferenceHypoalbuminaemiaSuggest recollection/repeat ammonia?Salicylate aetiology/levelHyperbilirubinaemiaCorrelate with clinical findingsMildly abnormal liver function testsLiver function tests not significantly

abnormal?Acetaminophen aetiology/level?Surgery/portal shunt?Chemotherapy effectNear normal albuminSuggest urine/blood drug/toxin screenSuggest ethanol levelsSuggest urine microscopy, culture and

sensitivityMonitor ammoniaUrea and electrolytes not significantly

abnormalUnlikely metabolic defect due to ageNormal ALT?Viral hepatitis/serologyDecreased proteinConsistent with severe liver disease?Muscle ischaemia/prolonged

immobilisationSuggest CRPSuggest repeat cTnI in 6–12 h?Primary/secondary malignancySuggest full blood examinationMonitor liver function tests?Hashimoto's encephalopathyCheck liver function tests / urea and

electrolytesMonitor blood gascTnI suggests myocardial injurySuggest chloride level?Random glucose resultLactate not significantly elevatedDo not monitor therapy with ammonia

levelsSuggest anion gapNormal bilirubinBorderline cTnIElevated cTnI due to stress responseRefer to clinical pathologistSuggest phosphateMild renal failure

Hyperlactataemia?Gastrointestinal haemorrhageUnlikely chronic liver disease?Urinary tract infectionMetabolic acidosis/compensatedHyperglycaemia?Carbamazepine aetiologySuggest BNP/?heart failureMarkedly increased lipase?Tumour of prostatePortal hypertensionNot consistent with hepatic encephalopathy

?Exogenous ammonia

Case 11-08 Liver



Clinical Notes on Request FormItchy

Case DetailsTotal Protein 70 g/L (60–81)Albumin 33 g/L (35–50)ALP 163 U/L (40–140)Total Bilirubin 8 μmol/L (<25)GGT 143 U/L (<51)AST 37 U/L (<41)ALT 47 U/L (<41)

Additional InformationSimilar results one month ago.

Suggested CommentThe liver enzyme pattern is consistent with focal cholestasis. Persistent increase in ALP and GGT in a woman with a history of itch suggests a diagnosis of primary biliary cirrhosis. Measurement of antimitochondrial antibodies (AMA) would be useful. Other causes of abnormal liver function tests such as ethanol and medications should be considered. Liver ultrasound may be helpful.

Rationale The combination of itch with raised cholestatic enzymes in a middle-aged woman raises the possibility of primary biliary cirrhosis (PBC), an autoimmune liver disease, which is characterised by the presence of antimitochondrial antibodies in the serum. Other autoantibodies such as anti-nuclear antibodies (ANA) may also be present in these patients. Serum immunoglobulin M, cholesterol and bile acids may be increased in advanced disease but these are not useful in early diagnosis. Many other conditions such as drug reactions, alcohol and primary sclerosing cholangitis (PSC) may be accompanied by increased cholestatic enzymes. Clinical suspicion for PBC and PSC are increased by the presence of other autoimmune disease and inflammatory bowel disease, respectively, The fact that the results were similar one month ago is reassuring but liver ultrasound may be useful to exclude a focal lesion in the liver such as a malignant tumour.

References1. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009;50:291-308. 2. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ

2005;172:367-79.



Liver function tests suggest cholestatic liver disease

Primary biliary cirrhosis ?Primary biliary cirrhosis?Primary sclerosing cholangitis?Alcoholic liver disease?Neoplastic liver disease?Autoimmune disease?Pruritus due to cholestasis?Intrahepatic cholestasis?Infiltrative liver diseaseSuggest anti-mitochondrial antibodiesExclude biliary obstruction/gall stonesSuggest hepatobiliary imagingSuggest autoantibodiesRequest drug history

HypoalbuminaemiaSuggest immunoglobulinsSuggest lipid studiesElevated ALP and GGTMildly elevated fiver function testsSuggest viral serologySuggest full blood examinationPersistent itch/middle aged womanLow albumin suggests chronic liver

diseaseNormal bilirubin levelPersistent moderately raised GGT?Obesity/diabetes mellitus/metabolic

syndromeSuggest renal function test and anion gap?Hodgkin's disease/lymphomaSuggest bile acidsSuggest AFPSuggest bone markers?CirrhosisRequest clinical historySuggest repeat/monitor liver function

tests?Chronic renal failure?Polycythaemia/haematologicalSuggest glucose?Fatty liver diseaseSuggest INR/APTTMildly elevated ALPAbnormal liver function tests?Pancreatitis/suggest amylase/lipaseHepatobiliary diseaseMildly elevated ALT?Thyroid disorder/suggest thyroid

function testsSuggest protein electrophoresis?Early Paget's diseaseConsistent with chronic obstructive

jaundiceSuggest gastroenterologist consultationLow alb/poor nutrition/increased lossNormal AST and ALTSuggest fat-soluble vitamins?Reference interval correct?Inflammatory bowel disease

? Chronic viral hepatitisExclude other causes of pruritus?Iron overload/suggest iron studiesSuggest liver biopsy?Infection?Hepatocellular injury?Primary biliary sclerosisHepatitis unlikelySuggest serum/urine osmolality?Cause not related to itch?Chronic infection?Wilson's diseaseSuggest serum copper/α1-antitrypsin Suggest ACE to exclude sarcoidosis

Case 12-09 Liver



Clinical Notes on Request FormRecent weight gain despite reduction in alcohol consumption.

Case DetailsTotal Bilirubin 17 μmol/L (<21)Total Protein 76 g/L (62–80)Albumin 44 g/L (38–48)ALP 63 U/L (30–130)GGT 136 U/L (≤60)ALT 59 U/L (5–55)AST 31 U/L (5–55)

Additional InformationSetting: General practice review as a component of Medicare incentive for chronic disease prevention.

Suggested CommentMild increases in GGT and ALT are consistent with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis if alcohol abuse is excluded. Consider obesity, insulin resistance, dyslipidaemia, drugs and continued alcohol use. Exclude common causes of hepatocellular liver damage. A small proportion of patients with this profile may progress to non-alcoholic steatosis and cirrhosis.

Rationale Mild increases in GGT and ALT are consistent with non-alcoholic fatty liver disease. Obesity, insulin resistance and dyslipidaemia are often associated with this condition, which may be confirmed by hepatic imaging. Drugs, continued alcohol use and common causes of hepatocellular liver damage, such as hypothyroidism should be excluded. A small proportion of patients may progress to non-alcoholic steatosis, fibrosis and cirrhosis but liver biopsy is not indicated unless the problem is severe or sustained. Weight loss, alcohol avoidance and review of medications are the most likely means by which results may be improved.

Reference1. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis:

selected practical issues in their evaluation and management. Hepatology 2009;49:306-17.



?Metabolic syndrome?Fatty liver disease?Non-alcoholic fatty liver disease?Non-alcoholic steatohepatitis?Continued alcohol intake?Drugs/medication?Iron storage disease/haemochromatosis?Hepatic steatosis ?Insulin resistanceSuggest lose weight, avoid alcohol, drugsSuggest hepatitis serologySuggest diabetes screenSuggest lipid profileSuggest thyroid function tests

?Elevated GGT due to alcoholLiver enzyme induction?AlcoholSuggest repeat in 1–3 monthsMildly elevated ALTMild hepatocellular damageElevated GGTSuggest hepatic imagingWeight gainWeight gain, increased GGT and slight increase in ALTMild elevation of GGT?Chronic viral hepatitis?Autoimmune diseaseMildly elevated GGT and ALT?ObesitySuggest cardiovascular risk assessment?Cirrhosis?Diabetes mellitus?ToxinsSuggest carbohydrate-deficient transferrinSuggest healthy active lifestyle?Other cause chronic liver disease?DyslipidaemiaSuggest albumin:creatinine ratioGGT may be raised for 1 monthNo routine comment?Herbal remediesSuggest urateRepeat after no alcohol and weight lossAST/ALT ratio <1 Suggest BMI

Mild non-specific hepatopathy?Infection?Increased appetite?Hepatobiliary diseaseSuggest morning cortisol?Advanced fibrosisSuggest full blood examinationSuggest liver biopsyNot hepatobiliary diseaseLowering of bilirubin

MISLEADING KEY WORDSALT, AST not significantly elevated

Case 13-01 Liver



Clinical Notes on Request FormRecent travel to the Middle East. Tiredness, lethargy, nausea and anorexia.

Case DetailsTotal Protein 74 g/L (60–82)Albumin 33 g/L (35–50)ALP 135 U/L (30–120)Total Bilirubin 96 μmol/L (<25)GGT 376 U/L (<50)AST 947 U/L (<41)ALT 3117 U/L (<51)LD 463 U/L (50–280)

Suggested CommentMarkedly raised transaminases are consistent with predominant hepatocellular damage. The enzyme pattern and recent travel history suggest viral hepatitis, particularly hepatitis A, as the most likely cause. Recommend serology to confirm the diagnosis. Paracetamol toxicity is less likely but should also be considered.

Rationale Marked elevation in AST and ALT with ratio <<1 suggests acute hepatocellular damage. The highest transaminase concentrations are seen in ischaemic/toxic liver damage and viral hepatitis. Recent travel to the Middle East suggests infection as the most likely aetiology and of the many possibilities; hepatitis A is the most common cause in this setting. Acute hepatitis can also be due to toxins and ischaemia although the AST/ALT ratio in these cases is usually >1.

Of toxins, paracetamol should be considered urgently due to time constraints for treatment, however in addition to the low AST/ALT ratio, the relatively low LD makes paracetamol toxicity less likely. Alcohol is less likely due to the low AST/ALT ratio. The relatively low LD and patient age make ischaemic causes unlikely. Autoimmune causes are possible but less likely with this degree of transaminase elevation and should be considered only when the more likely causes have been excluded.

Reference1. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005:172

367-79.



Predominantly hepatocellular pathologyLiver function tests suggest viral hepatitisLiver function tests suggest hepatitic

pictureResults consistent with parenchymal liver

disease?Cytotoxic liver damageHepatocellular disease Low AST/ALT ratio-viral origin/acuteExclude paracetamol toxicityALT and AST markedly elevatedResults consistent with acute hepatitisConsider hepatitis A?Acute hepatitis?Infectious hepatitisExclude viral hepatitisSuggest hepatitis serology (A,B,C,D,E)Exclude drug/toxin/herbal induced?Drug/toxin/herbal inducedSuggest repeat liver function testsPhone results to referring doctor

?EBV, CMV, Coxsackie, HSVSuggest coagulation profileSuggest full blood

examination/differentialSome degree of cholestasisSuggest renal functionSuggest HIV serologyExclude ischaemic liver damageCholestasis and reduced synthetic abilitySuggest iron studiesSuggest serum copper and

caeruloplasminSuggest α1-antitrypsin, anti-smooth

muscle antibodies?Acute cholangitisRaised GGT consistent with cytotoxic

damage?Accompanying haemolysisSuggest indirect bilirubin?LeptospirosisIschaemic liver damage less likelyLess common EBV, CMV, Coxsackie,

herpes simplex 1 virus

?Autoimmune hepatitisSuggest malaria study/thick and thin film?Alcohol induced?Wilson's diseaseSuggest amoebic serology?Acute on chronic infectionLow albumin metabolismSuggest glucose levelSuggest ultrasound of hepatobiliary system

Raised liver function tests consistent with alcohol/toxins

Suggest hepatology reviewSuggest schistosomiasisExclude Katayama feverSuggest rickettsial studiesSuggest ethanol levelExclude parasitic infectionsSuggest toxoplasmosisSuggest radiology for lesionsSuggest urine drug screen?Dengue fever/?Q feverSuggest blood culturesSuggest stool examinationExclude hypoxia?Secondary to cholestatic jaundiceExclude fatty acid oxidation disorder - suggest acylcarnitine

?Brucellosis?Yellow fever?TyphoidExclude biliary obstructionSuggest carbohydrate-deficient transferrin

Case 14-08 Liver


Patient Location Intensive Care Unit

Clinical Notes on Request FormGastric ulcer.

Case DetailsGGT 79 U/L (<60)ALP 51 U/L (30–110)ALT 3349 U/L (<55)AST 2325 U/L (<45)LD 4219 U/L (110–230)Bilirubin 6 μmol/L (2–24)Albumin 13 g/L (34–48)

Additional InformationUrea 23.5 mmol/L (2.7–8.0)Creatinine 83 μmol/L (50–100)Hb 63 g/L (115–155)

Suggested CommentMarked elevation in transaminases suggests acute hepatitis. Drug effects and hypoxia should be considered. Viral hepatitis is less likely due to significantly raised lactate dehydrogenase (LD) and normal bilirubin. Markedly low albumin may include effect of recent gastrointestinal bleed but protein-losing states should be excluded. Recommend coagulation studies and search for underlying conditions, particularly paracetamol and other medications, heart failure and sepsis.

Rationale Hypoxic hepatitis (HH) occurs in up to 1% of ICU admissions. Mortality is over 50% during hospitalisation and 25% after one year, and is related to underlying medical conditions. The diagnosis of HH requires (1) clinical setting of acute cardiac, respiratory or circulatory failure; (2) a sharp but transient increase in serum aminotransferases activity, reaching at least 20 times the upper reference limit; (3) exclusion of other causes of acute liver cell necrosis, particularly viral or drug-induced hepatitis. Contrary to expectation, shock was absent in around half of reported HH patients. Severe blood loss alone is not usually sufficient to cause HH. In more than 90% of cases, the patient has a severe underlying pathology, particularly heart failure and septic shock. Renal failure is common (15–65% of cases) and is an independent marker of poor prognosis due to organ hypoperfusion. Of note, the elevated urea is likely the result of catabolism of the haemoglobin from the gastric ulcer.

Massive elevation in transaminases due to paracetamol poisoning typically occurs 2 to 5 days after ingestion, when the paracetamol concentration is usually undetectable. A careful history of paracetamol ingestion, including slow release forms, is the best diagnostic approach.

Reference1. Henrion J. Hypoxic hepatitis. Liver Int 2012;32:1039-52.



Marked elevation of transaminasesSevere anaemiaAcute hypoxic liver injuryAcute hepatitisViral hepatitis unlikely Consistent with upper gastrointestinal

tract (GIT) bleed?Massive bleed - gastric ulcer?Ischaemia?Drugs, alcohol or toxinsSuggest coagulation studiesReview drug history?Hypoperfusion due to blood lossPoor prognosisInvestigate low albumin

Elevated ureaElevated lactate dehydrogenase (LD)HypoalbuminaemiaLow haemoglobinSuggest hepatitis serology?Viral hepatitisHepatocellular damageClinical history notedNormal creatinineNormal bilirubinSuggest full blood count?Severe shockNormal ALP?Impaired hepatic synthesis?Haemorrhagic shockLiver function tests acute/chronic

impairmentSuggest electrolytesElevated urea/creatinine ratioMildly elevated GGTProbable hepatic necrosisConsistent with hepatitisCholestasis unlikely?Pre renal acute kidney injuryMonitor liver function testsRule out helicobacter pylori infectionDissociation urea and creatinineCorrelate with clinical history?Hyperlactataemia?EncephalopathySuggest renal function testsHepatic liver function tests patternSuggest lactate and glucoseNon-obstructive pictureSuggest total protein

Suggest paracetamol levels?Acute liver failure?Autoimmune hepatitis?MalignanciesSuggest arterial blood gasIsolate bleed/transfuse?Haematological disorder?Perforated gastric ulcerSuggest endoscopySuggest creatine kinase?Mucosal erosion in GITSuggest amylase?Zollinger-Ellison syndrome


?Chronic liver diseaseSuggest liver ultrasoundSuggest gastrin?Muscle injurySuggest lipaseSuggest haptoglobin?Nephrotic syndromeSuggest faecal occult bloodSuggest urine protein?Hepatic dysfunctionExclude haemoglobinopathy

Case 8-07 Enzymes


Patient Location Cardiology

Clinical Notes on Request FormPast history of heart valve replacement.

Case DetailsTotal Bilirubin 12 μmol/L (3–20)ALP 66 U/L (30–115)AST 36 U/L (<40)ALT 25 U/L (<40)GGT 45 U/L (5–65)LD 481 U/L (100–225)

Additional InformationHb 134 g/L (110–160)HcT 0.41 (0.34–0.47)RCC 4.5 x 1012 (3.7–5.4)Retic 33 x 109 (10–100)MCV 93 fL (80–100)WCC 8.7 x 109 (3.5–10.0)

Suggested CommentThe elevated lactate dehydrogenase (LD) may be due to intravascular haemolysis caused by the prosthetic heart valve. The normal reticulocyte count, haemoglobin and bilirubin levels indicate that the haemolysis is mild. Suggest monitor to ensure condition is stable, or consider other causes of raised LD, if clinically indicated.

Rationale A mild degree of intravascular haemolysis is common among patients (prevalence 50–90%) with normally functioning prosthetic heart valves and is attributed to mechanical destruction of red blood cells. Clinically significant haemolysis is rare and occurs mainly with malfunctioning valves accompanied by paraprosthetic valvular regurgitation (1). Elevated serum lactate dehydrogenase (LD) activity in patients with prosthetic heart valves is well documented and correlates with the level of haemolysis (2). Depending on the degree of haemolysis there may be an increase in the reticulocyte count, serum bilirubin and a reduction in serum haptoglobin. However, LD is a non-specific marker and can be raised due to delayed separation, myocardial infarction, liver disease, skeletal muscle disease and malignancy. In this case, a full clinical history and the appropriate choice of tests should assist with the diagnosis.

References1. Ismeno G, Renzulli A, Carozza A, et al. Intravascular hemolysis after mitral and aortic valve

replacement with different types of mechanical prostheses. Int J Cardiol 1999;69:179-83.2. Mansuroğlu D, Omeroğlu SN, Izgi A, et al. LDH levels and left atrial ultrastructural chances in patients

with mitral paraprosthetic regurgitation. J Card Surg 2005;20:229-33.



Subclinical haemolysis?Haemolysis Consistent with prosthetic valve

replacementHaemolysis due to heart valve?Intravascular haemolysisSuggest cardiac markers (troponin,

creatinine kinase)

Increased LDSuggest serum haptoglobinNormal full blood countBilirubin normal?Myocardial injury?Collection artefact?Myocardial infarctionHepatic enzymes normalSuggest clinical evaluation?Muscle damageSuggest blood filmElevated LD non-specificNormal reticulocyte countMonitor test resultsResults not typical of haemolysisOther results normal?Paravalvular leakage/dysfunctionNo anaemia - haemoglobin normalCheck if sample haemolysed?Pulmonary embolus?Other haematological disordersSuggest repeat LDLD unlikely liver originSuggest renal function tests?Cell injury/inflammationSuggest potassium?Macro-LD?Due to warfarin therapyCheck previous LD resultsCheck INRCheck haemolysis indexSuggest platelet countNo megaloblastic anaemia?Myocardial disease

?MalignancySuggest LD isoenzymes?Kidney or lung damageIntravascular haemolysis unlikelyIncreased AST:ALT/high ASTNo commentSuggest investigations for malignancySuggest urine Hb/haemosiderin?Hypothyroidism?Liver disease?Type of valveIsoenzymes not indicatedNot iron deficiency anaemiaSuggest Schumm testNot due to liver disease or haemolysisDue to aspirin therapySuggest C-reactive protein

Case 8-08 Enzymes

Patient ID 16-month-old male


Clinical Notes on Request FormPost upper respiratory tract infection

Case DetailsSerum

Sodium 144 mmol/L (135–145)Potassium 4.5 mmol/L (3.5–5.0)Chloride 109 mmol/L (97–107)Bicarbonate 19 mmol/L (20–28)Urea 4.8 mmol/L (1.8–7.5)Creatinine <20 µmol/L (30–70)Glucose, random 4.7 mmol/L (3.6–7.7)Protein 63 g/L (60–75)Albumin 38 g/L (35–50)Globulin 25 g/L (15–25)T Bilirubin 3 µmol/L (3–20)ALP 5150 U/L (60–300)AST 29 U/L (25–80)ALT 14 U/L (5–40)GGT <5 U/L (5–65)LDH 294 U/L (100–405)

Suggested CommentIn the absence of liver or bone disease the isolated marked elevation of the alkaline phosphatise (ALP) in this child makes the diagnosis of benign transient hyperphosphatasaemia of infancy and childhood likely. Suggest ALP isoenzyme testing and repeat ALP in 2–3 months.

Rationale The clinical history of an isolated marked elevation of alkaline phosphatise (ALP) in a young child after a viral infection makes the diagnosis of benign transient hyperphosphatasaemia (BTH) of infancy and childhood likely. The occurrence of BTH is not rare, and is mainly seen in winter. Most patients with BTH present during the first year of life. It is associated with a wide variety of clinical disorders, including gastrointestinal diseases, respiratory infections, congenital anomalies/inborn errors of metabolism, anaemia, and malignancies. The differential diagnosis includes liver (such as biliary obstruction, and liver disease associated with malignancy) and bone diseases (such as juvenile Paget’s disease or rickets). In patients with BTH, ALP-isoenzyme electrophoresis shows increases in bone and liver ALP and ALP typically returns to normal in 2–3 months. In the Australian setting, it was seen in a third of children with increased ALP >1000 U/L in a tertiary-care teaching hospital. In the community setting the likelihood of BTH of infancy would be much higher.

References1. Stein P, Rosalki SB, Foo AY, et al. Transient hyperphosphatasemia of infancy and early childhood:

clinical and biochemical features of 21 cases and literature review. Clin Chem 1987;33:313-8.2. Behúlová D, Bzdúch V, Holesová D, et al. Transient hyperphosphatasemia of infancy and childhood:

study of 194 cases. Clin Chem 2000;46:1868-9.3. Carroll AJ, Coakley JC. Transient hyperphosphatasaemia: an important condition to recognize. J

Paediatr Child Health 2001;37:359-62.



Isolated increased ALP?Benign transient hyperphosphatasaemia

of infancy (BTHI)BTHI seen in young childrenBTHI often post infectionExpect normal ALP <3 monthsExpect normal ALP in 3–6 monthsResolves spontaneously?Familial hyperphosphatasaemia?Bone disease excluded?Liver disease excludedConsider vitamin D deficiencySuggest repeat ALP ≤3 monthsSuggest ALP isoenzymesMonitor ALPSuggest follow-upConsider rickets

Suggest calcium/phosphateSuggest clinical evaluationOther liver function tests normalSuggest vitamin D/PTHLikely bone originRepeat ALP 3–6 monthsLow creatinine?ALP due to viral illnessRepeat ALPMild metabolic acidosisCreatinine consistent with low muscle

massSuggest screen family members?Healing fractureNo further investigation requiredConsult with Chemical PathologistSuggest consult specialistRepeat liver function tests?Malnutrition?Renal diseaseMarginally low bicarbonateElevated chloride?GGT artefactual

?MalignancyNot hepatic originSuggest magnesium?Paget’s disease?Medication-inducedRepeat GGT?Creatinine interference, suggest repeatSuggest bone turnover markerSuggest CT/X-ray?Chronic respiratory alkalosisConsider hyperparathyroidismLikely leukocyte originSuggest white cell count/diff?OsteomyelitisSuggest liver ultrasoundReye’s syndrome unlikelyRepeat full blood countSuggest urinalysisSuggest blood gasesSuggest serology testingIntestinal originMay be due to growth spurtConsider bone scan

Case 9-01 Enzymes



Clinical Notes on Request FormAbdominal pain.

Case DetailsSerum lipase 5169 IU/L (13–60)

Additional InformationSerum

Protein 77 g/L (65–85)Albumin 42 g/L (34–47)T Bilirubin 27 µmol/L (<22)ALP 131 U/L (30–120)GGT 362 U/L (10–71)ALT 46 U/L (5–40)Adjusted Ca 3.19 mmol/L (2.10–2.60)Glucose 19.2 mmol/L (3.0–7.7)

Suggested CommentMarked elevation of lipase together with abdominal pain is likely caused by acute pancreatitis. A C-reactive protein concentration might provide prognostic information. Hyperglycaemia early in the course of the pancreatitis may resolve. The main causes of pancreatitis are gallstones and alcohol; hypercalcaemia is rarely the cause of acute pancreatitis and needs to be further investigated.

Rationale Marked elevation of lipase together with abdominal pain is likely caused by acute pancreatitis. A lipase of >3 times the upper reference limit has a diagnostic specificity of about 98% for pancreatitis. The magnitude of lipase elevation is a poor prognostic indicator. Severity of the pancreatitis can be assessed using a number of scoring systems, the most popular being the APACHE II. An APACHE II score of ≥8 is associated with significant mortality risk. A CRP concentration >150 mg/L provides further prognostic information.

Hyperglycaemia early in the course of the pancreatitis may be due to acute pancreatic dysfunction. Later, it is a marker for disease severity. The main causes of pancreatitis are gallstones and alcohol; hypercalcaemia is rarely the cause of acute pancreatitis and needs further investigations. While hypercalcaemia increases the risk for pancreatitis, additional gene mutations might contribute to the absolute risk. The elevated GGT is not helpful in diagnosing alcoholic pancreatitis with an AUC of 0.51 for this purpose (3). The ALT is not elevated enough to indicate a gallstone aetiology (4). Of note, the diagnosis of diabetes mellitus using random fasting glucose requires 1) glucose of ≥11.0 mmol/L, and 2) classical symptoms of hyperglycaemia or hyperglycaemic crisis. The diagnosis of diabetes mellitus should not be made in a patient who is systematically ill.

References1. Lankisch PG, Burchard-Reckert S, Lehnick D. Underestimation of acute pancreatitis: patients with only

a small increase in amylase/lipase levels can also have or develop severe acute pancreatitis. Gut 1999;44:542-4.

2. Working Party of the British Society of Gastroenterology, et al. UK guidelines for the management of acute pancreatitis. Gut 2005;54:iii1-9.

3. Methuen T, Kylänpää L, Kekäläinen O, et al. Disialotransferrin, determined by capillary electrophoresis, is an accurate biomarker for alcoholic cause of acute pancreatitis. Pancreas 2007;34:405-9.

4. Tenner S, Dubner H, Steinberg W. Predicting gallstone pancreatitis with laboratory parameters: a meta-analysis. Am J Gastroenterol 1994;89:1863-6.

5. Felderbauer P, Karakas E, Fendrich V, et al. Pancreatitis risk in primary hyperparathyroidism: relation to mutations in the SPINK1 trypsin inhibitor (N34S) and the cystic fibrosis gene. Am J Gastroenterol 2008;103:368-74.



Significantly elevated lipaseConsistent with acute pancreatitis?Secondary to alcoholHypercalcaemia may cause pancreatitisGlucose - endocrine pancreatic

dysfunction?HyperparathyroidismSuggest PTHInvestigate raised calciumSuggest fasting lipidsHypertriglyceridaemia may cause

pancreatitis?Secondary to gallstonesSuggest CRP

Hypercalcaemia noted?Cholestatic/biliary diseaseHyperglycaemiaElevated GGTHyperglycaemia due to

stress/inflammationLiver function tests abnormalitiesSuggest fasting plasma glucose/GTT post

resolutionSuggest renal function tests, eGFRDiabetes mellitus not excludedSuggest radiology chest/abdomen?Chronic pancreatitis?DrugsSuggest full blood examination, LDHAcute on chronic pancreatitisSuggest phosphateSuggest ionised calciumRepeat calciumLiver function tests and plasma glucose

secondary to pancreatitis?Diabetic ketoacidosis?Calcium infusion therapyLiver function tests suggest hepatobiliary

diseaseSuggest blood gases for acidaemiaExclude renal failureNo evidence lipaemiaRepeat liver function testsCalcium lower after first day?Antacids cause hypercalcaemiaPossible acute pancreatitis

Suggest amylase (lipase:amylase)?Malignancy in pancreasPancreatitis may cause hypercalcaemia?Diabetic nephropathySuggest vitamin D?Raised calcium due to dehydration?PseudohyperparathyroidismSuggest urinary albumin, protein?Pancreatic glucagonomaLiver function tests suggest hepatocellular disease

Myeloma excludedGlucose suggests diabetesMalignancy causing hypercalcaemia

Case 12-01 Enzymes



Clinical Notes on Request FormPreviously raised CK, 5 months ago.

Case DetailsCK 242 U/L (<150)LD 220 U/L (110–230)

Additional InformationAlbumin 42 g/L (34–48)Globulins 35 g/L (21–41)Protein 77 g/L (65–85)Total bilirubin 11 µmol/L (2–24)GGT 13 U/L (<60)ALP 41 U/L (30–110)ALT 30 U/L (<55)AST 33 U/L (<45)

5 months earlier:CK 465 U/L (<150)LD 246 U/L (110–230)

Suggested CommentPersistent mild elevation in creatine kinase (CK) suggests muscle damage, probably of skeletal origin. Troponin, which is a more specific marker for cardiac muscle injury may be considered, if clinically suspected. Possible causes of a raised CK of this level include medications (especially statins), hypothyroidism, exercise, myositis, or metabolic conditions. Macro-CK may produce this pattern and should be screened for if other causes cannot be identified. Recommend TSH and review of medication initially.

Rationale Mildly (<10× upper reference limit) raised creatine kinase (CK) is a common laboratory finding. Most of these normalise upon repeat testing, after asking the patient to refrain from exercise and alcohol consumption. Up to 11% of patients on statins have CK in this range; CK increase is dose-dependent and may be exacerbated by exercise or other medications. To meet prescribing criteria for a statin, patients should have an increased risk of cardiac disease, so it is not possible to rule out an acute coronary syndrome (ACS) in the absence of clinical notes. It is important to exclude common clinical problems such as ACS, medication or hypothyroidism before recommending more extensive investigations such as testing for macro-CK or muscle biopsy. Nonetheless, a considerable number of patients with persistently elevated CK have subclinical neuromuscular pathology demonstrable on histology or electromyography, although most of these conditions are benign.

References1. Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with

asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002;249:305-11.

2. Dabby R, Sadeh M, Herman O, et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006;8:110-3.



Persistent elevation of CKSkeletal muscle origin cannot be

excluded?Skeletal muscle origin?Skeletal myopathies?Myositis?Myopathy?Muscle trauma/injury/surgery Exclude statinsExclude exercise/excess/?athleteExclude hypothyroidismReview medication, ?drug associatedExclude thyroid abnormalities/suggest

thyroid function tests

Consider macro-CKSuggest CK isoenzymes-electrophoresisExclude cardiac sourceElevated CKNormal AST/LDIsolated CK elevationCheck medical history?Clinical features of muscle disorderExclude alcohol excessMild elevation of CK?Muscular dystrophy carrierExclude inflammation/infectionNormal liver function testsModerately elevated CKSuggest ANA/exclude systemic lupus

erythematosus?Kidney disease/renal function?Metabolic myopathySuggest electrolytes, ?hypokalaemiaSuggests non-cardiac sourceSuggest complete blood picture/ESR/filmSuggest monitor CK?Family history of muscular dystrophySuggest calcium/phosphate?Clinically consistent - phone to discussMyocardial injury unlikelySuggests muscle origin?Polymyalgia rheumatica?Periodic paralysisSuggest transaminase assayElevated CK consistent with muscle

damageCheck occupational historyConsider forearm ischaemic testSuggests non-skeletal muscle origin

?Intramuscular injection?Muscular dystrophy?Rhabdomyolysis/suggest myoglobinSuggest cortisol?Seizures?Brain origin?Malignancy e.g. colon, kidneyNo comment and/or CK <1000 U/LSuggest specialist referral?Rheumatoid arthritis?Guillain-Barre syndromeSuggest DNA genetic markersSuggest fasting lipid screenSuggest vitamin D Exclude malignant hyperthermia?Neuroleptic malignant syndrome?Coeliac disease


Consider muscle biopsySuggest electromyographyExclude diabetic ketoacidosis/suggest blood glucose

Suggest metabolic bone studies

Case 13-02 Enzymes



Clinical Notes on Request FormChronic alcoholic

Case DetailsAmylase 1530 U/L (<100)Lipase 49 U/L (<60)

Additional InformationRenal and liver function tests requested. Elevated GGT, otherwise no abnormalities.

Suggested CommentElevated serum amylase with normal lipase. This may be due to an extra-pancreatic source of amylase such as parotid disease, which can be clarified by measurement of pancreatic and salivary amylase. Macroamylase should also be considered. If parotid inflammation is not present clinically then exclusion of macroamylase by measurement of urine amylase or other technique is recommended.

Rationale Amylase and lipase are both elevated in cases of pancreatitis, although amylase tends to rise and fall sooner than lipase. In alcoholic patients, lipase has a higher clinical sensitivity for pancreatitis than amylase. Serum amylase is made up of two main types. The P-type amylase comes from the pancreas while the S-type amylase comes from the salivary glands. Causes of elevated amylase without elevation of lipase include secretion from other organs such as salivary glands, fallopian tubes and cyst fluid, gastrointestinal tract, testes, lungs, thyroid, tonsils, and some malignant neoplasms. Of note, acute pancreatitis secondary to hypertriglyceridaemia may not be associated with elevations in serum amylase.

The laboratory can contribute to the management of this patient by excluding the presence of macroamylase, which are amylase enzymes with autoantibodies attached to them. This may be performed by measuring urine amylase (normal in macroamylase due to size exclusion by glomerulus, and elevated in other causes), polyethylene glycol (PEG) precipitation or other separative methods. Pancreatic amylase can be measured, and when it is not elevated, confirms an extra-pancreatic source. In this patient the pancreatic amylase was within normal limits, and was consistent with parotitis as the source of elevated amylase.

Reference1. Harper SJ, Cheslyn-Curtis S. Acute pancreatitis. Ann Clin Biochem 2011;48:23-37.



Elevated amylase with normal lipasePancreatitis unlikelyConsistent with non-gastrointestinal

cause?Macroamylasaemia?Alcohol related salivary amylase?Salivary amylase?Parotiditis?Acute abdominal conditionSuggest amylase isoenzymesSuggest amylase clearance ratio (ACCR)Suggest urine amylaseSuggest pancreatic amylaseSuggest PEG precipitation or gel

filtration

?Clinical symptomsSuggest repeat testingSuggest imaging?Active biliary diseaseMay be seen in acute pancreatitisResults phonedConsistent with chronic alcoholism?Pancreatic pseudocyst

?Neoplastic diseaseIncreased GGT consistent with clinical notes

?Renal failure?Anti-epileptic medicationSuggest lipid studies?Alcoholic pancreatitis?Pancreatitis?Heterophile antibodies?Head injury/stroke?Diabetic ketoacidosisLipase inhibited by bile acids?Alcohol intoxicationResult not phonedSuggest protein electrophoresisConsistent with chronic pancreatitisSuggest reanalysis on different instrument

Case 14-07 Enzymes


Patient Location Pre-admission outpatient clinic

Clinical Notes on Request FormAwaiting elective surgery for cholecystectomy. Family history of prolonged post-surgical apnoea.

Case DetailsTotal Bilirubin 32 µmol/L (<21)Albumin 37 g/L (38–48)Total Protein 62 g/L (62–80)GGT 158 U/L (<35)ALT 65 U/L (5–55)AST 71 U/L (5–55)Butyryl-cholinesterase 5 kU/L (6–14)

Additional InformationFurther inquiry reveals that the family history consisted of a brother who required prolonged ventilation after receiving an anaesthetic that included suxamethonium.

Suggested CommentThe family history raises the possibility of hereditary butyryl-cholinesterase deficiency. This should be investigated further by genotyping. Phenotyping of the enzyme with inhibitors such as fluoride and dibucaine is being phased out because it is less reliable. The possibility of prolonged post-anaesthetic apnoea should be communicated to the surgical and anaesthetic team. The increase in serum bilirubin, aminotransferases and glutamyltransferase is consistent with causes of liver dysfunction including cholelithiasis. Borderline reduction in serum albumin and total protein is consistent with mild impairment of hepatic synthetic capacity, so measurement of international normalised ratio (INR) is suggested. Cholelithiasis alone is insufficient explanation for the observed reduction in the activity of butyryl-cholinesterase, but other causes of reduced hepatic synthesis can cause this degree on butyryl-cholinesterase reduction.

Rationale Butyryl-cholinesterase (pseudocholinesterase) is an enzyme produced by the liver, circulating in the plasma. Its activity is a sensitive marker of hepatic synthetic capacity. It is also a specific indicator of the adequacy of the enzyme that is required for the catabolism of a number of xenobiotic compounds, including suxamethonium. Suxamethonium, or succinylcholine, is a nicotinic acetylcholine receptor agonist commonly used to induce muscle relaxation before intubation in anaesthesia. In normal individuals, approximately 90–95% of an intravenous dose of suxamethonium is metabolised by circulating plasma butyryl-cholinesterase before reaching the neuromuscular junction. Deficiency of this enzyme can result in high concentration of suxamethonium reaching the neuromuscular junction. This causes prolonged paralysis of up to 8 hours. The activity of the enzyme in the plasma is inhibited by organophosphate insecticide toxicity. Conditions such as uncomplicated cholelithiasis, cholestasis or mild cirrhosis rarely diminish its activity.

Butyryl-cholinesterase can decline following major acute illnesses and in malnutrition, or when hepatic synthesis declines in the face of acute hepatitis, cirrhosis or hepatic metastasis. Less severe decline can occur in the presence of muscular dystrophy, chronic renal disease and pregnancy. The family history raises the possibility of hereditary butyryl-cholinesterase deficiency, which should be investigated further by genotyping because phenotyping of the enzyme with inhibitors such as fluoride and dibucaine fails to fully characterise the presence and pattern of hereditary enzyme deficiency.

Reference1. Yen T, Nightingale BN, Burns JC, et al. Butyrylcholinesterase (BCHE) genotyping for post-

succinylcholine apnea in an Australian population. Clin Chem 2003;49:1297-308.



Low cholinesterase level/ activityBorderline butyryl-cholinesterase

deficiencyFamily history of suxamethonium apnoeaInherited suxamethonium apnoea?Risk of post suxamethonium/scoline

apnoeaAvoid suxamethonium/ mivacurium/

succinylcholineNotify anaesthetist/surgeon?Pseudocholinesterase deficiencyCholestasis/biliary obstructionSuggest family genotyping Suggest

repeat butyryl-cholinesterase when liver function tests normal

Suggest screening of relativesSuggest genotyping on brotherSuggest phenotyping and genotypingSuggest genotypingSuggest screening of relativesSuggest cholinesterase genotypingSuggest phenotyping OR genotypingAvoid curare-derived drugsMild impairment hepatic synthetic

capacitySuggest INR/PT?MalnutritionNeed pre-op review by surgical team

?Low cholinesterase due to liver diseaseRaised serum bilirubin, AST and GGTSuggest phenotypingBorderline low cholinesteraseHypoalbuminaemia?Biliary stones/ cholelithiasisSuggest ALP, bilirubin, AST, GGT and

lipase?Renal diseaseConsider drug/alcoholHepatocellular damage?Acquired cholinesterase deficiency?Genetic variant?Exposure to organophosphatesSuggest urea, electrolytes, creatinineSuggest genotyping if required?Possible suxamethonium/

succinylcholine sensitivitySuggest medical warning card?Chronic/acute hepatitisAbnormal cholinesterase phenotype?Alcoholic liver diseaseSuggest full blood countSuggest repeat liver function tests post op?HypothyroidismSuggest repeat cholinesteraseInhibition test maybe inconclusive

?UraemiaSteatohepatitisAutoimmune/viral hepatitis?DiabetesSuggest ultrasound?Liver cirrhosis?Oestrogen therapyLow cholinesterase can’t be due to liver disease

Consistent with cholecystitis


Suggest renal function test?Collagen disease

Case 14-09 Cardiac



Clinical Notes on Request FormChest pain since morning. To exclude acute myocardial infarction.

Case DetailsCollection Time Result Reference Interval

Troponin I 11:30pm <2 ng/L <16 ng/L

Additional InformationPast medical history: nil of note.ECG, urea, electrolytes and creatinine and full blood examination normal.Troponin performed on Abbott Architect by hs-TnI assay; 10% CV at 6 ng/L.

Suggested CommentAn undetectable troponin measured with a high sensitivity assay more than 6 hours after onset of chest pain in the absence of clinical and/or electrocardiogram (ECG) evidence would indicate a low probability of acute myocardial infarction (AMI). Suggest repeat measurement in 2–3 hours if clinically indicated.

Rationale The third universal definition of acute myocardial infarction (AMI) requires the detection of a rise and/or fall of a cardiac biomarker above the 99th percentile of a reference population (15 ng/L in this case) together with evidence of ischaemia (clinical symptoms, electrocardiogram changes or imaging evidence for loss of viable myocardium). The major advantage of high sensitivity-cardiac troponin (hs-Tn) assays is to allow the earlier exclusion of AMI in emergency departments in low risk patients presenting with chest pain. Diagnostic sensitivity approaching 100% may be achieved by measuring a second sample within three hours of presentation and 6 hours of onset of pain.

An accelerated diagnostic protocol suggests that a TIMI (thrombolysis in myocardial infarction) score of ≤1, a normal ECG and troponin at 0- and 2-hours in patients presenting <12 hours after onset of pain will safely rule out an AMI. Whilst an undetectable hs-cTnT at presentation has very high negative predictive value, which may be considered to rule out AMI in low risk patients, this has not been shown with hs-cTnI assays. Ultimately, the decision for repeat measurement/s has to be guided by clinical presentation. The actual infarction (luminal occlusion) may occur at any stage from symptom onset. Hence, if this occurred just prior to presentation (which may have prompted the late presentation), then a single sample at presentation may miss the rise in troponin.

References1. Cullen L, Mueller C, Parsonage WA, et al. Validation of high-sensitivity troponin I in a 2-hour

diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol 2013;62:1242-9.

2. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol 2011;58:1332-9.

3. Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252-7.



No rise in TnI 12 h post chest painResult positive if ≥16 ng/LTnI not elevated within 6 h of symptomsLow probability of AMIAcute myocardial infarction (AMI)

unlikelyMyocardial injury is unlikelyExclude AMIIf TIMI score 0 or 1 repeat at 2 hSuggest repeat 2–3 h post sample collectSuggest TnI 2–3 h post presentationSuggest repeat TnI in 2 hSuggest repeat TnI after 3 hSuggest repeat hs-TnI after 3 h Suggest

repeat 4 h post first sampleSuggest repeat troponin I (TnI) in 3–6 hClinical correlation recommendedExclude other causes for chest painRise and/or fall required for diagnosisIf repeat normal, AMI unlikelyFor MI TnI >upper reference limit (URL)

at 3 or 6 h and >50% changeExclude stable coronary ischaemia

Normal TnIResults provided exclude AMINormal ECGSuggest repeat 6–8 h post chest pain?Pulmonary infection/inflammationResults do not exclude AMISuggest repeat ECGSuggest lipid profileSuggest repeat TnI at 3 and 6 hConfirm non-ST elevation myocardial

infarction (NSTEMI; rise TnI >50% URL)

?Clinical suspicionFollow local guidelines50% increase in TnI suggests cardiac Exclude pericarditisResult negative if <16 ng/L and change

<50%Exclude other acute coronary syndromeSuggest serial 6 h TnI, CK or myoglobin?Heterophilic Ab on original TnISuggest re-run sample-use different

methodSuggest further investigations for

unstable anginaSuggest observe patientSuggest repeat testing at 9–12hrs ?>30% rise at 4 h post first sampleSuggest D-Dimer?Aortic aneurysm?Chest/lung pathologySuggest BNP/NT-proBNPSuggest exercise tolerance testing?StressTn may take ≥6 h to rise post pain A <30% delta Tn is less likely AMI?Pulmonary embolism

Exact time of chest pain not given?Digestive disorderSuggest repeat with TnT assay within 24 h

?Musculoskeletal chest painRepeat TnI not indicatedReference interval should be <6 ng/L?Breast pathologySuggest thoracic scanFalsely low TnI with high Hb concentration

Suggest creatine kinase (CK)/CK-MBSuggest liver function tests/creatinineSuggest C-reactive proteinSuggest microbial cultures

Case 12-06 Proteins



Clinical Notes on Request FormBack pain

Case DetailsSerum Protein Electrophoresis:

IgG (kappa) monoclonal band detected.Quantification: 3 g/L

Additional InformationIgG 7.3 g/L (6.5–14.5)IgA 0.8 g/L (0.7–3.5)IgM 0.6 g/L (0.6–2.6)

X-ray of spine, full blood count, ESR and liver function tests are unremarkable.

Suggested CommentSmall IgG (kappa) band with probable mild immune paresis is of uncertain significance at this time. Recommend first morning urine for electrophoresis and serum free light chains measurement. Serum calcium, renal function tests and skeletal survey should also be done for completeness. While monoclonal gammopathy of undetermined significance (MGUS) is likely, clinical consideration of oligosecretory conditions e.g. amyloid is important. Suggest review of serum and urine by electrophoresis initially in 3 to 6 months.

Rationale The small band size, heavy chain type IgG and the lack of anaemia, and normal x-ray of the spine all point to MGUS. Mild immune-paresis is not incompatible with this diagnosis, nor is the presence of free light chains in urine were these to be found. The diagnosis of MGUS can only be made when serum monoclonal protein is <30 g/L, clonal bone marrow plasma cells <10% (if performed) and there is absence of hypercalcaemia, renal impairment, anaemia and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder. Therefore, serum calcium, renal function tests and skeletal survey are required. Smouldering multiple myeloma is defined by serum monoclonal protein ≥30 g/L and/or ≥10 to <60 percent bone marrow clonal plasma cells and absence of CRAB complications.

While the overall progression rate to myeloma is 1% per year, the monoclonal band size is the most potent predictor for progression and this band is very small. IgG band types are also less likely to progress than IgA or IgM types. While bone marrow biopsy is part of the classification, this is probably unnecessary at this band size unless CRAB are positive, in which case the diagnosis is myeloma regardless of band size. Small monoclonal bands can sometimes be associated with other lymphoproliferative disease. Of these, systemic Amyloid Light-chain (AL) amyloidosis is often diagnosed late; clinical suspicion and serum free light chains are important for timely diagnosis. On available data, this patient appears to be at low risk for progression; however, indefinite follow up is essential. A short repeat time is prudent in the first instance and initial check periods of up to 6 months are suggested in various guidelines.

References1. Mollee P. Current trends in the diagnosis, therapy and monitoring of the monoclonal

gammopathies. Clin Biochem Rev 2009;30:93-103.2. Cook L, Macdonald DH. Management of paraproteinaemia. Postgrad Med J 2007;83:217-23.



Small monoclonal band ?significanceBorderline immuneparesis of

immunoglobulinsLow normal IgG, IgA, IgM?Suppression of polyclonal

immunoglobulinNo signs of bone marrow failure?MGUS?Primary lymphoproliferative disorder?AL amyloidosisResults suggest MGUSMultiple myeloma unlikely Exclude multiple myelomaSuggest urine Bence Jones Protein/urine

protein electrophoresisSuggest serum creatinine, urea &

creatinineSuggest serum calcium/phosphate levelsSuggest serum free light chains (FLC

ratio)Suggest follow up testingSuggest skeletal survey/?lytic lesionsSuggest urine immunofixation

electrophoresisContinue to monitor ?progressionClinical correlation requiredUse same lab for consistencySuggest regular clinical review

Suggest beta-2-microglobulinSuggest serum

electrophoresis/immunofixationSuggest urine protein/albumin excretion?History of auto-immune disease e.g.

rheumatoid arthritisMonoclonal band - benign paraprotein?Type of clonal gammopathyIgG discrepancy due to monoclonal

proteinBack pain common in multiple myelomaElevated risk of progression to multiple

myeloma

Suggest bone marrow biopsySuggest liver function testsSuggest complete blood count/ESRSuggest CRPSuggest urine microscopy, culture and

sensitivity testingExclude nephropathy/urinary tract

infectionReferral to Haematologist?Multiple myelomaNo immuneparesis?Smouldering multiple myeloma?Inflammation/infection?Solitary plasmacytomaSuggest phenotype of plasma cells


MGUS unlikelyNo evidence suggestive of B cell lymphoma

Results suggest polyclonal globulins raised

No comment on these results?MacroglobulinaemiaExclude free light chains only myeloma?Waldenstrom’s macroglobulinaemia

Case 13-04 Proteins



Clinical Notes on Request Form34 weeks gestation. Hypertension.

Case DetailsProtein 47 g/L (64–83)Albumin 18 g/L (36–46)Total bilirubin 5 µmol/L (<20)ALP 113 U/L (35–105)ALT 6 U/L (<33)GGT <5 U/L (<38)Uric acid 0.50 mmol/L (0.14–0.34)

Suggested CommentThe presence of hypertension beyond 20 weeks gestation increases the risk of pre-eclampsia, which also requires evidence of end organ or foetal involvement. Although hyperuricaemia is common in this disorder, it is not diagnostic. The significant hypoproteinaemia may indicate proteinuria and should be investigated with a urinary protein:creatinine ratio. Full blood examination and ultrasound assessment of the pregnancy are also suggested but should not delay urgent clinical review in a hospital setting.

Rationale Pre-eclampsia is a multi-system disorder characterised by hypertension and the involvement of one or more organ systems and/or the foetus. Complications may include renal and liver impairment; haematological manifestations of haemolysis or disseminated intravascular coagulation; seizure and other neurological disturbances; pulmonary oedema; foetal growth restriction and placental abruption. The condition can arise de novo or be superimposed on chronic or gestational hypertension.

Findings such as hyperuricaemia and oedema, while common in this disorder, are not diagnostic features. Similarly, proteinuria is frequently seen but not required for diagnosis. Urgent clinical assessment is essential as management is influenced by severity of hypertension and clinical findings in mother and foetus. Although some women will be managed as an outpatient, initial assessment should be performed as an inpatient. In the long term, women with history of pre-eclampsia or gestational hypertension are at increased cardiovascular morbidity.

References1. Brown MA, Lowe SA. Current management of pre-eclampsia. Med J Aust 2009;190:3-4.2. Society of Obstetric Medicine of Australia and New Zealand. Guidelines for the management of

hypertensive disorders of pregnancy 2008. http://www.somanz.org/pdfs/somanz_guidelines_2008.pdf

http://www.somanz.org/pdfs/somanz_guidelines_2008.pdf



HypoproteinaemiaHypoalbuminaemiaHypertension associated with gestation?Pre-eclampsia?Proteinuria?Renal loss Suggest spot urine protein/albumin/

creatinineSuggest complete blood examinations

including platelet countSuggest 24h urine protein/albumin/

creatinineSuggest urine proteinSuggest urgent specialist referralSuggest clinical review/monitorSuggest ultrasound/foetal assessmentPhone GP

HyperuricaemiaALP consistent with gestationHypertensionHospital (emergency) admissionSuggest coagulation profileReview to pregnancy reference intervalsMonitor renal function tests?Nephrotic syndromeMonitor blood pressureMonitor haemolysisMonitor liver function test and lactate

dehydrogenase?HELLP syndromeGestational related oedema?Protein lossSignificant abnormal resultsMonitor plateletsRisk of early deliveryRaised ALT in preeclampsia?Early onset preeclampsiaQuantification of proteinuria?Perinatal riskExclude HELLPPre-eclampsia depends on level of blood

pressure and total proteinResults consistent with gestational

proteinuric hypertension/pre-eclampsia?Hypertension nephropathy

Monitor oedemaMonitor urine outputOliguriaSuggest free T4 and TSHSuggest repeat sampleSuggest Doppler blood flow studiesUrine microscopy hyaline/granular castsMonitor proteinuria


Protein and albumin consistent with gestation

Liver function tests normal for gestation

Case 6-07 Lipids



Clinical Notes on Request FormNausea and vomiting

Case DetailsTotal Cholesterol 13.5 mmol/L (<5.5)Triglyceride 38.5 mmol/L (<1.7)

Additional InformationAlbumin 26 g/L (35–50)Bilirubin 60 µmol/L (<20)Alk. Phosphatase 254 U/L (35–135)ALT 300 U/L (<40)

Suggested CommentMarked hypertriglyceridaemia and hypercholesterolaemia in a setting of abnormal liver function tests. Suggest exclude secondary causes such as diabetes, alcohol abuse and obesity. There is an increased risk of pancreatitis due to high triglyceride concentrations. Suggest measure lipase or amylase levels.

Rationale Lipid disorders can occur as either a primary event or secondary to some underlying disease. Severe hypertriglyceridaemia may be due to the rare (<1 in a million) disorder lipoprotein lipase deficiency. Other rare genetic conditions with a similar presentation include apoC-II and apoA-V deficiency (1).

Secondary causes of severe hypertriglyceridaemia are more common. They are often due to a combined genetic defect and an acquired condition resulting in an overproduction and delayed clearance of triglyceride-rich lipoproteins. Such acquired conditions include diabetes mellitus, alcohol abuse and obesity. The abnormal liver function tests in this case suggest liver disease secondary to alcohol abuse is a likely cause. Evidence suggests when triglyceride concentrations are >11 mmol/L, there is an increased risk of chylomicron-induced pancreatitis and therefore either an amylase or lipase test should be performed (2).

Of note, hypothyroidism, nephrotic syndrome, dysgammaglobulinaemia, cholestatic disorders of the liver, anabolic steroids and protease inhibitor for HIV treatment are associated with elevated total cholesterol and LDL. On the other hand, elevated triglycerides and VLDL may be due to underlying chronic renal failure, type 2 diabetes mellitus, obesity, excessive alcohol intake and hypothyroidism, oestrogen and corticosteroid (endogenous or exogenous) effects.

References1. Viljoen A, Wierzbicki AS. Diagnosis and treatment of severe hypertriglyceridemia. Expert Rev

Cardiovasc Ther 2012;10:505-14. 2. Ferns G, Keti V, Griffin B. Investigation and management of hypertriglyceridaemia. J Clin Pathol

2008;61:1174-83.



Marked hypertriglyceridaemiaMarked hyperlipidaemiaAbnormal liver function tests?Secondary hyperlipidaemia?EthanolExclude pancreatitisExclude diabetes/suggest glucoseSuggest lipase/amylase?Clinical historyPhone GP to discuss results

Liver diseaseHypercholesterolaemia?Familial/primary hyperlipidaemia?Obstructive liver disease?Hepatitis/toxinCholestasisSuggest lipoprotein electrophoresis

/ApoE genotypeUrgent referSuggest hepatitis serologyAcute pancreatitisSuggest INR/coagulation studiesPathologist review?Chronic liver diseaseSuggest viral serology?Acute illnessNo comment

Repeat on fasting sampleSuggest other liver function testsSuggest TSH/thyroid function testsSuggest electrolytes/renal function testsSuggest HDL/LDL/apolipoproteinsLipaemic sample - interferenceExcess VLDL and ?chylomicronsSuggest stat urine protein?Fatty liverElevated risk of coronary diseaseSuggest dietary/medication treatmentUrgent hepatic ultrasound?Obesity/metabolic syndromeSuggest liver biopsyRepeat tests 6–8 weeksSuggest full blood examinationSuggest immunoglobulin quantitationSuggest calciumSuggest ammonia/lactate/blood gasesModerate cholesterolaemiaSuggest lipowash/ultracentrifugationSuggest CK/troponinI/ ECG?HepatomaSuggest anti mitochondrial antibody?Cushing’s disease/suggest cortisol

Case 7-08 Lipids



Clinical Notes on Request FormCheck-up

Case DetailsPlasma lipids (patient was fasting)

Cholesterol 6.0 mmol/LTriglyceride 0.5 mmol/LHDL-cholesterol 3.7 mmol/LLDL-cholesterol 2.1 mmol/L

Additional InformationDesirable NHFTarget Target

Cholesterol <5.5 <4.0Triglyceride <2.0 <1.5HDL-cholesterol >1.0 >1.0LDL-cholesterol <3.0 <2.0

Suggested CommentThe increased total cholesterol is due to the increased HDL-C, which is usually considered to be cardioprotective, although not necessarily in all cases. The LDL-C is within the desirable target. Oestrogen therapy, alcohol intake, and genetic causes may be contributory factors. Suggest review in context of absolute cardiovascular risk status.

Rationale The reason for the ‘check-up’ in this patient is not stated in the request. Lipid screening is not indicated in a healthy 33-year-old woman unless she belongs to a high-risk group that includes patients with diabetes mellitus, previous personal/family history of atherosclerotic disorders, smoking history, hypertension and obesity (1). Cardiovascular risk management should be based on absolute risk assessment of the patient. Thus knowledge of the presence or absence of evidence of atherosclerosis or other risk factors is important in advising action on lipid results.

HDL is more tightly controlled by genetic factors (which determine 40–50% of the variation) than for the other lipoproteins. In general, plasma HDL concentration is inversely correlated with the prevalence and mortality rates for coronary heart disease. However, emerging evidence suggests that HDL are heterogeneous particles and their quality (functional or physical subclasses), rather than simply absolute concentration, may be more important in their cardioprotective effects. Environmental factors causing a high HDL-C include oral oestrogen therapy (by ~20%), alcohol consumption (by ~0.1 mmol/L) and extensive aerobic exercise (by 3–9%).

Oestrogens, depending on the type, dose and route of administration, increase synthesis of the principal apoprotein of HDL, apoA-I. In general, progestagens oppose these effects according to type and dose. Fibrates increase HDL-C by 10–25%, statins by 5–15%, and niacin by 20–35%. The rare genetic deficiency of CETP is associated with a high HDL, especially in the Japanese; others include apoA-I mutations. The HDL concentration in this case may be due to genetic and environmental factors including endogenous oestrogens. Reassurance is appropriate for a patient with a raised HDL trait who is asymptomatic with no other risk factors.

Reference1. U.S. Preventive Services Task Force. Screening for Lipid Disorders in Adults.

http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm



Total cholesterol predominantly HDLLDL-C & triglyceride desirableHDL cardio-protectiveGood lipid profileHDL:LDL/Chol ratio good Low cardiovascular riskReview clinical risk factors?On E2 Rx/pregnant?Alcohol abuse

Total cholesterol above targetElevated HDL-CSuggest repeat tests 2–24 months?Familial (hyperalphalipoproteinaemia)?Other drugs?Family history of cardiovascular disease?Excessive exerciseAcceptable if not high risk group?CETP deficiencySuggest liver function tests?On lipid medicationSuggest CHD risk calculatorSuggest Apo A &/ B levelsSuggest confirm resultsTreatment not indicatedTargets vary with clinical riskNo comment

Suggest low cholesterol diet/dieticianSuggest thyroid function testsSuggest lifestyle changes?HypothyroidismIncreased cardiovascular riskSuggest glucose/diabetes lxIncreased cardiovascular risk with very high HDL

Consider lipid drug Rx?Diabetes?Renal disease?Pre-/analytical errorSuggest renal function tests?Polycystic ovarian syndromeAim for lower total cholesterol on treatment

Suggest follow-up relativesSuggest lipoprotein(a)Suggest CK?Cholestasis

http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm

Case 8-03 Lipids



Clinical Notes on Request FormNon-alcoholic steatohepatitis (NASH) for a number of years. BMI=38.

Case DetailsCholesterol 7.4 mmol/LTriglycerides 2.0 mmol/LLDL-cholesterol 4.7 mmol/LHDL-cholesterol 1.8 mmol/L

Additional InformationNot on any medication.

Suggested CommentRaised total and LDL-cholesterol and a history of NASH are both associated with increased risk of cardiovascular disease. Exclude secondary causes of hypercholesterolaemia and perform a full cardiovascular risk assessment. Lifestyle interventions to increase exercise and promote weight loss are recommended.

Rationale Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disease from steatosis to NASH, cirrhosis, and rarely hepatocellular carcinoma may develop as a complication. Prospective studies have shown that survival with NASH is reduced from cardiovascular- and liver-related causes. NAFLD is strongly associated with obesity and insulin resistance and other features of the metabolic syndrome. This is a case of a severely obese lady with documented NASH and lipid studies showing raised total and LDL-cholesterol. The lipid results in this case are not typical of metabolic syndrome (low HDL and raised triglycerides), making it important to exclude treatable secondary causes, in addition to doing a full cardiovascular risk assessment. Although insulin resistance is central to NAFLD, routine insulin measurement is not helpful. Regression of histological features of NASH has been demonstrated with weight loss.

Reference1. Riley P, O’Donohue J, Crook M. A growing burden: the pathogenesis, investigation and management

of non-alcoholic fatty liver disease. J Clin Pathol 2007;60:1384-91.



Predominantly hypercholesterolaemiaUndesirable LDL-CIncreased risk of cardiovascular diseaseExclude secondary causes?Hypothyroidism Suggest fasting glucoseSuggest diet/lifestyle reviewSuggest review of cardiovascular risk factors

Suggest thyroid function tests

Obesity/high BMICombined hyperlipidaemia?Insulin resistance/glucose intoleranceNote history of NASHConsistent with steatohepatitis/NASHSuggest liver function tests Refer to Lipid GuidelinesRepeat fasting lipid profileSuggest lipid-lowering medicationHypertriglyceridaemiaSuggest monitor lipidsHigh risk of Type 2 diabetes?Patient fastingSuggest OGTTSuggestion of metabolic syndrome?Familial causesConsider metabolic syndromeHDL-C level associated with low risk?Nephrotic syndrome?CholestasisSuggest apolipoproteinsSuggest review by specialistRisk of cirrhosisSuggest urine protein?Pregnancy?Alcohol intake?Other metabolic problemsSuggest urea, creatinine & electrolytesHDL-C due to ethanolSuggestion of insulin resistance

Lipid ratio suggests low risk?Polycystic ovary syndromeTriglyceride level low riskSuggest insulin levelNormal LDL-C and HDL-CSuggest lipid electrophoresisCardiac risk ratio - low riskSuggest androgen levels?Pancreatic disease

Case 9-02 Lipids



Clinical Notes on Request FormUnwell. Dizzy.

Case DetailsTotal protein 69 g/L (62–83)Albumin 33 g/L (33–47)Bilirubin 35 µmol/L (<20)AST 368 U/L (10–45)ALT 144 U/L (5–45)ALP 580 U/L (40–110)GGT 6728 U/L (10–70)LD 435 U/L (100–200)

Additional InformationNa 140 mmol/L (135–145) Urea 3.1 mmol/L (3.0–8.0)K 4.3 mmol/L (3.2–4.5) Urate 0.45 mmol/L (0.15–0.50)Cl 102 mmol/L (100–110) Gluc 5.2 mmol/L (3.6–7.7)Bicarb 25 mmol/L (22–33) Lipase 164 U/L (25–300)Anion gap 13 mmol/L (5–15) Chol 30.2 mmol/L (2.6–3.5)Creatinine 80 µmol/L (50–110) Trig 168.4 mmol/L (0.5–2.0)

Suggested CommentThe extremely elevated GGT and increased AST/ALT ratio suggest alcohol-related liver disease. The marked hypertriglyceridaemia confers an increased risk of acute pancreatitis. A combination of a secondary cause on a genetic background of dyslipidaemia (lipoprotein lipase and apoC-II deficiency) is a possible cause of the marked hypertriglyceridaemia. Two secondary causes, diabetes mellitus and renal disease, can be presumptively excluded by the normal random glucose and creatinine. Other secondary causes of hyperlipidaemia, including obesity, alcohol and drugs should be sought. Suggest measure the lipid profile after treatment when the patient is in better health.

Rationale This patient presented with massively increased triglycerides and liver function test results that suggest alcohol or drug related liver disease. Although there are many secondary causes of hypertriglyceridaemia that require exclusion, most do not produce such gross elevations, raising the possibility of a primary dyslipidaemia aggravated by a secondary insult. Hypertriglyceridaemia (>10 mmol/L) is associated with an increased risk of pancreatitis, and is the most common cause of acute pancreatitis not due to alcohol or gallstones, accounting for 7% of all cases. Moreover, hypertriglyceridaemia is a (non-major) risk factor for cardiovascular disease.

Reference1. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ

2007;176:1113-20.



Marked elevation of GGTMixed cholestatic and hepatitic patternMarked hyperlipidaemiaMarked hypertriglyceridaemiaAST/ALT ratio >2?Alcoholic liver disease?Alcohol-induced dyslipidaemia?Primary dyslipidaemia?Drugs/medications?Hepatic steatosis?Lipoprotein lipase/apoCII deficiency?DysbetalipoproteinaemiaConsistent with alcoholic hepatitisIncreased risk pancreatitisDrug/alcohol historySuggest APOE genotypingHyperlipidaemia requires further

investigationLipaemia expected to improve with

abstinence

Raised liver function testsSuggest repeat fasting lipidsExclude hypothyroidism?Diabetes mellitusSuggest lipoprotein electrophoresis?Increased lipids 2° to liver disease?Obstructive biliary diseaseSuggests chronic liver diseaseSuggest imaging/ultrasound?Cholestatic liver diseaseIncreased GGT/ALP?Neoplasm/liver tumourPredominately cholestatic liver function

testsSuggest blood ethanolExclude nephrotic syndromeSuggest full blood count/ coagulationSuggest amylaseSuggest hepatitis serologySuggest lipoprotein profile?Cardio/cerebro vascular diseaseSuggest clinical review/family historyNo evidence pancreatitisSuggest HDL/LDL cholesterol

measurementSuggest apolipoprotein A/BIncreased ratio triglyceride/cholesterol?Increased chylomicrons/VLDL

remnants?Viral hepatitisPancreatitis not excluded?Familial combined hyperlipidaemiaSuggest other specialised lipid testsSuggest VLDL/chylomicron

measurement?Familial combined lipoproteinaemiaSuggest troponinSuggest iron studySuggest AFP/HCG/PSASuggest carbohydrate-deficient

transferrinRepeat lipaseSuggest CKSuggest LD isoenzymesRaised LD?Familial hypertriglyceridaemia?Lipoprotein X?Obesity-induced dyslipidaemiaNon-alcoholic fatty liver diseaseAssess cardiovascular risk factorsExclude primary biliary cirrhosisExclude other causes of liver disease?Cholangitis?Pancreatitis?HepatosplenomegalyIncreased triglycerides interferes with

?Non-fastingSuggest oral glucose tolerance testPossible factitious lipids?Dietary cause for increased lipidsConsistent with acute pancreatitisRecollect sampleConsider biopsyNo commentExposure to petrochemical solvents

lipase measurementMonitor liver function tests?Gall stonesRepeat liver function tests in 3 days?XanthomataHyperlipidaemia increases risk of

diabetes mellitus, coronary heart disease?Zieve’s syndrome?Infiltrative liver diseaseExclude haemolysis

Case 12-05 Lipids


Patient Location Medical Outpatient

Clinical Notes on Request FormDiabetes; lipid monitoring

Case DetailsResult Target

Total Cholesterol 5.9 mmol/L <4.0Fasting Triglyceride 5.5 mmol/L <2.0HDL Cholesterol 1.02 mmol/L >1.0LDL Cholesterol 2.1 mmol/L <2.5

Additional InformationOn therapy with Metformin and Sulphonylurea

Suggested CommentConfirm fasting status and consider secondary causes, especially alcohol use and renal impairment. Predominant hypertriglyceridaemia consistent with type 2 diabetes. Despite meeting target concentrations, the HDL-C is low for female gender. LDL-C was measured directly because the Friedewald equation is invalid if triglycerides exceed 4.5 mmol/L. Although LDL-C meets target for uncomplicated diabetes, it is likely to underestimate cardiovascular disease (CVD) risk in the presence of raised triglycerides. Consider non-HDL-Cholesterol (Total – HDL-C), or apoB as preferred CVD risk markers in the presence of raised triglycerides.

Rationale The moderate predominant hypertriglyceridaemia is adequately explained by the presence of type 2 diabetes, but alternative causes should be considered and excluded. Exacerbation may cause progression to severe hypertriglyceridaemia. The HDL target is based on the bottom of the reference interval for men. Women have concentrations that are about 30% higher than men. Women with diabetes may lose their gender-specific protection from CVD.

When triglycerides exceed 4.5 mmol/L, the presence of chylomicrons becomes more likely. They differ from VLDL in terms of composition, so the Friedewald equation no longer applies. Direct measurement of LDL-C is required. When triglycerides are elevated, cholesterol ester transfer protein acts to reduce HDL-C and transform LDL into small dense LDL. These small dense LDL have less cholesterol per particle, but do more damage per particle. In these circumstances, LDL-C will underestimate CVD risk.

There is one apoB per atherogenic particle, so this is the best way to measure harmful lipoproteins when LDL has been confounded by elevated triglycerides. Non-HDL-Cholesterol (Total – HDL-C) is the next best option.



High triglycerides may affect LDL resultHigh triglycerides may affect HDL result Consistent with diabetic dyslipidaemiaConfirm fasting specimen?Poorly controlled diabetic?Alcohol excess?Renal involvement / suggest renal function tests

Consider fibrate therapyAssumed LDL measured not calculatedExclude secondary causes

HypertriglyceridaemiaSuggest modify lifestyleClinical history notedHigh risk of cardiovascular diseaseSuggest HbA1cTarget levels different in diabetesSuggest lipid lowering therapyHypercholesterolaemiaOptimise glucose controlSuggest cardiovascular disease risk

assessment?Patient obese?Hypothyroidism / suggest thyroid

function testsRefer to relevant guidelinesSuggest urine microalbuminReview medicationModerate hypertriglyceridaemiaRefer National Heart Foundation

GuidelinesSuggest ApoE phenotypingElevated cholesterol/HDL ratio?Levels secondary to diabetesHDL target >1 mmol/LLDL target <2 mmol/LTriglycerides target <1.5 mmol/LMild hypercholesterolaemiaBorderline HDL levelSuggest lipoprotein electrophoresisMarked hypertriglyceridaemiaTotal cholesterol target <4 mmol/L?SmokingRequest previous resultsSuggest glucoseConsider statin therapyReduced HDL-CHyperlipidaemia?Liver disease?Insulin resistance/metabolic diseaseTriglycerides target <2 mmol/LMildly elevated triglyceride?Frederickson type IVNormal LDL/HDL ratio 2.06LDL target <2.5 mmol/LLDL target <2 if coronary heart disease

presentHighest risk LDL<2.0 HDL>1.0

triglycerides <1.5High risk LDL<2.5 HDL>1.0

triglycerides <1.7Elevated triglycerides/HDL ratio

Monitor lipids?Type III hyperlipidaemia?Patient complianceRequest further clinical historySuggest baseline CK levels/liver function tests

?Autoimmune / steroidsLDL above diabetes target value?Increased intermediate density lipoprotein

?Commence insulinModerate hypercholesterolaemiaRefer to Framingham Risk Tables?Familial dyslipidaemiaConsider niacin therapyConsistent with Fredrickson Type IIb pattern

Suggest insulin/OGTTMarked cholesterolaemiaSuggest familial defective apoB100 mutation

Normal risk TC<5.5 LDL<3.5 HDL>1 triglycerides <1


Normal LDL CholesterolNormal HDL Cholesterol

Case 13-09 Lipids



Clinical Notes on Request FormGeneral check prior to embarking on plans to become pregnant

Case DetailsTotal Cholesterol 7.9* mmol/L (≤5.2)HDL Cholesterol 1.4 mmol/L (1.0–2.5)Fasting Triglyceride 1.6 mmol/L (≤2.0)LDL Cholesterol 5.7* mmol/L (≤3.0)

Additional InformationCreatinine 69 μmol/L (50–90)Total bilirubin 7 μmol/L (0–18)Alkaline Phosphatase 56 U/L (0–145)AST 28 U/L (5–55)ALT 34 U/L (5–55)GGT 14 U/L (0–40)Creatine Kinase 106 U/L (0–175)TSH 0.65 mU/L (0.35–5.5)

Suggested CommentMarked hypercholesterolaemia due to LDL accumulation. Many secondary causes, including hypothyroidism, anorexia and cholestasis, are not supported by intercurrent results. Assess family history and signs (corneal arcus, tendon xanthomas), estimate Dutch Lipid Clinic Score and calculate absolute risk of cardiovascular disease. Consider familial hypercholesterolaemia and genetic testing. Cholesterol concentrations are likely to increase in the event of pregnancy but pharmacological treatment is contraindicated.

Rationale Familial hypercholesterolaemia (FH) is a prevalent genetic cause of increased LDL cholesterol concentrations due to mutations in any of several genes (LDLR, APOB, PCSK9) that affect the LDL receptor pathway. The condition accelerates the progression of atherosclerosis so that cardiovascular disease (CVD) events occur 20 to 40 years sooner. Affected individuals are recognised by the presence of elevated LDL cholesterol concentrations, a dominant family history of high cholesterol and premature CVD, and the variable presence of cholesterol accumulation in other tissues. Total cholesterol is a poor discriminator in later age, but elevated concentrations in young patients are suggestive. The likelihood of FH is best evaluated by applying the Dutch Lipid Clinic Score. Cases of probable or definite FH warrant consideration of confirmatory genetic testing with genetic counselling to facilitate Family Cascade Screening.

Reference1. Watts GF, Sullivan DR, van Bockxmeer FM, et al. A model of care for familial hypercholesterolaemia:

key role for clinical biochemistry. Clin Biochem Rev 2012;33:25-31.



Raised LDL-CNormal liver/thyroid/renal function tests?Familial hypercholesterolaemiaCheck family historyRisk of coronary heart disease?Tendon xanthoma?Corneal arcus Refer Dutch Lipid Clinic criteria?Primary hypercholesterolaemia?Familial Defective ApoB-100Suggest genetic screeningExclude anorexia nervosaLipids increase in pregnancyExclude statins during pregnancy

Suggest monitor/change lifestyleExclude nephrotic syndromeAssess cardiovascular disease riskHypercholesterolaemiaSignificant hypercholesterolaemiaSuggest repeat lipid studiesSuggest serum/urine total protein,

albumin, globulinsHypothyroidism unlikely?Oral contraceptive/oestrogen pillsConsult specialistNormal triglyceride and HDLCholestasis unlikely?Polycystic ovarian syndromeNephrotic syndrome unlikelyManage with Familial

Hypercholesterolaemia Australasia Network Consensus

?Isolated hypercholesterolaemia?Familial combined

hyperlipoproteinaemiaExclude pregnancyExclude nephrotic syndrome and

cholestasisConsistent with Frederickson Type IIaRaised cholesterol and HDL ratioMonitor thyroid function tests during

pregnancyCheck post-partumManage with National Vascular Disease

Prevention Alliance GuidelinesPregnancy not contraindicated

Exclude diabetes mellitusSuggest fasting glucose?Medications/alcoholSuggest thyroid function testsRisk of pre-eclampsia?HypothyroidismSuggest urea, creatinine, electrolytes, liver function tests and CRP

Suggest full lipid studiesRisk of hypertensionExclude Cushing's syndromeRisk of preterm birthSuggest oestrogen, FSH, LH, prolactin, 17-ketosteroids

?Secondary hypothyroidismSuggest albumin:creatinine ratioSuggest repeat lipid studies 1–6 months?Secondary hypercholesterolaemia?HypergammaglobulinaemiaSuggest serum electrophoresis?Dysglobulinaemias?Metabolic disorderExclude insulin resistance syndromeSuggest serum insulinRepeat lipid studies in 3 monthsSuggest assess pituitary functionRefer to New Zealand Guidelines


Suggest lipid lowering drugsRisk of atherosclerosis in infantLower lipids pre-pregnancySuggest statins

Case 6-03 Thyroid



Clinical Notes on Request FormSubclinical hypothyroidism, repeat as suggested.

Case DetailsTFTs Free T4 14 pmol/L (10–23)

TSH 3.4 mIU/L (0.40–4.00)

Additional InformationFasting Plasma

Cholesterol 4.5 mmol/LTriglyceride 1.3 mmol/LGlucose 4.9 mmol/L

Previous Results:Free T4 12 pmol/LTSH 4.1 mIU/L

Suggested CommentBorderline TSH persists. Consider repeating in one year with thyroid autoantibodies (TPO antibodies).

Rationale TSH has an intra-individual (day-to-day) biological variability of 19.7%. Incorporating this biological variability, the 95% confidence interval of any TSH result is ±40%, and higher if analytical variability is also considered. Therefore, both TSH results are borderline with respect to the upper reference limit. Similarly, population studies have failed to separate TSH levels of >2.5 mIU/L from levels of >4.0 mIU/L when predicting future development of hypothyroidism. TSH exhibits diurnal variation, peaking at night during sleep and decreasing by 50% by 8 a.m. and remains relatively constant until late afternoon, when a smaller trough occurs. The afternoon trough often disappears in disease. The diurnal variation is probably of little relevance to routine testing as blood sampling occurs mostly during the nadir. Elevated TSH concentrations are often seen in the elderly, with the 97.5th percentile increasing by 0.3 mIU/L/decade of life after 30–39 years old. In older population, mild elevation in TSH may represent natural aging process instead of pathology.

Subclinical hypothyroidism is characterised by TSH above upper reference limit and a normal free T4. The risk of progression to overt hypothyroidism is about 2–3% per year, but this increases significantly when TPO antibodies are positive. Although increased cardiovascular risks have been described in patients with subclinical hypothyroidism, the lack of prospective controlled trial means treatment on this basis remains debatable. However, thyroxine replacement should be considered in patients with TSH >10 mIU/L, symptomatic for hypothyroidism, positive TPO antibodies, or evidence of atherosclerotic cardiovascular disease, heart failure, or risk factors associated with these diseases. Guidelines for subclinical hypothyroidism generally suggest assessment of TPO antibody and yearly monitoring.

Reference 1. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: co-

sponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012;18:988-1028.



Normal thyroid function testsPrevious results borderline Suggest monitor thyroid function testsSuggest anti-TPO Abs

TSH high normalRisk developing hypothyroidism?Subclinical hypothyroidismNormal lipids and glucoseNo comment?ThyroiditisSubclinical hypothyroidism unlikely?Transient hypothyroidismBorderline low thyroid function tests?Previous non-thyroidal illnessAssess cardiovascular disease riskNormal fasting glucose?Diurnal variation effectHistory notedResults similar to previousNo treatment required?Non-thyroidal illness?Goitre?Clinical historyPrevious results - ? other causesNo further actionTransient compensated hypothyroidNo clinical risk TSH <10

Suggest clinical examNon-steady state thyroid function testsAim lower cholesterol targetSuggest T4 replacementSuggest FT3T4 replacement effective?Drug-induced TSHRepeat glucose and lipids?Suboptimal replacement?Age-relatedSuggest lipids and cardiac markers?Reference range of 1st resultsSuggest thyrotropin releasing hormone stimulation test

Assay CV checkedConsider T4 replacement

Case 8-04 Thyroid



Clinical Notes on Request FormFeeling tired and lethargic.

Case DetailsFree T4 20 pmol/L (9–19)TSH 0.02 mIU/L (0.40–4.00)Free T3 5.5 pmol/L (3.0–5.5)

Additional InformationNot on any medication.

Suggested CommentThe suppressed TSH and high-normal free T4 and free T3 suggest hyperthyroidism, commonly due to Graves’ disease; less common causes are thyroiditis, nodular thyroid disease and surreptitious thyroxine intake. TSH-receptor antibodies and thyroid scan may be useful. However, low TSH may be found in early pregnancy, which should be excluded. If the patient is pregnant, repeat thyroid function tests in 6 weeks.

RationaleThe combination of a suppressed TSH (<0.l mIU/L) and borderline/raised free T3 and free T4 concentrations suggests hyperthyroidism (due to Graves’ disease, thyroiditis, or surreptitious T4 intake). TSH-receptor antibodies and thyroid uptake scan may be indicated. However in a woman of childbearing age pregnancy should be considered, as TSH may be lowered in the first trimester of pregnancy, although such extremes of TSH and free T4 (in response to a significantly increased hCG) are usually seen in the hyperemesis group. If she was found to be pregnant, the tests should be repeated in 6 weeks’ time. If free T4 and free T3 were clearly elevated as opposed to borderline in a pregnant woman, then the diagnosis would be gestational thyrotoxicosis, which warrants treatment.

Reference1. UK Guidelines for the Use of Thyroid Function Tests.

http://www.acb.org.uk/docs/TFTguidelinefinal.pdf



Suppressed TSHBorderline/elevated free T4Borderline/elevated free T3Consistent with hyperthyroidismConsider early/borderline

hyperthyroidismConsider subclinical hyperthyroidism?Thyroiditis?Graves’ disease?Pregnant?Recent thyroxine ingestion?Thyroid nodules?Ingestion of iodine Suggest thyroid antibody studiesRepeat thyroid function tests 1-3 monthsSuggest thyroid scan

Consider non-thyroid illnessRepeat thyroid function tests?GoitreRepeat thyroid function tests 3-6 months?Thyroid diseaseRepeat thyroid function tests <1 monthSuggest follow-up/reviewMonitor thyroid function tests regularly?Non-T4 medication?Patient post-partum?Treated thyroid diseaseRecommend hCGTSH not fully suppressedSymptoms not consistent with

hyperthyroidismSuggest erythrocyte sedimentation rateSuggest thyroglobulinNormal free T4Consistent with euthyroidismSuggest endocrine reviewSuggest specialist review?Positive thyroid antibodies

Suggest clinical examination?Pituitary dysfunctionSuggest glucoseSuggest thyroid ultrasound scanResolved thyrotoxicosisSuggest FSH/LH/PRL/GH/ACTHSuggest liver function tests and lipids?Ingestion of caffeineSuggest TRH?Immune-deficient

Case 10-05 Thyroid



Clinical Notes on Request Form32/40 pregnant, headache.

Case DetailsFree T4 21.2 pmol/L (10.0–19.0)TSH <0.03 mIU/L (0.50–4.00)Free T3 4.3 pmol/L (3.5–6.5)

Additional InformationSerum hCG: 5710 IU/L

Suggested CommentAssuming the subject is not on thyroxine, the TSH is suppressed and free T4 inappropriately elevated for a woman of this gestational age. This is not hCG driven and is suggestive of subclinical thyroid pathology such as Graves’ disease. Suggest measure thyroid antibodies including thyroid-stimulating antibodies and be vigilant for potential complications of pregnancy.

Rationale It is tempting to interpret the results given as normal for pregnancy, although this is not the case. During early pregnancy, the reference interval for thyroid-stimulating hormone (TSH) is lower than in non-pregnant women, although this returns to the pre-pregnancy range by the third trimester. Human chorionic gonadotrophin (hCG) concentrations increase during the first trimester, peaking between 7 and 13 weeks. hCG has mild TSH-like activity, leading to slightly increased free T4 during early pregnancy and in turn, leading to a feedback decrease in TSH with balanced thyroid function.

When the hCG elevation or activity is exaggerated, it will lead to the syndrome of gestational transient hyperthyroidism (or thyrotoxicosis, if symptomatic), which is seen in 2.5–11% of pregnant women. This is characterised by mildly increased free T4 and suppressed TSH. It is usually associated with hyperemesis gravidarum and spontaneously resolves within 2-3 weeks. It can be distinguished from Graves’ disease by the absence of thyroid ophthalmopathy, thyroid antibodies (particularly TSH receptor antibodies) and transient nature of the illness. The TSH suppression and elevated free T4 are abnormal for the present case (at 32 weeks gestational age), and are suggestive of thyroid pathology. Moreover, the lower hCG concentration seen in this case (appropriate for gestational age) could not account for the pattern of thyroid function observed. With Graves' disease there is an increased risk of complications of pregnancy, and small increased risk of neonatal thyrotoxicosis, although not usually seen with this degree of abnormality.

Anti-thyroperoxidase autoantibodies (TPOAb) are the most sensitive test for thyroid autoimmune disease, including Graves’ disease. Anti-thyroglobulin autoantibodies (TgAb) test is less sensitive and is generally not used for this purpose. Measurement of anti-TSH receptor autoantibodies (TRAb) is a quantitative test for Graves’ disease, whilst thyroid-stimulating immunoglobulin (TSI) is a bioassay test that characterises the stimulating effects of TRAb. An elevated TRAb/TSI helps differentiate Graves’ disease from gestational thyrotoxicosis in the first trimester. Women with Graves’ disease and negative TRAb are highly unlikely to result in foetal hyperthyroidism. By contrast, high titres of TRAb in pregnancy require careful foetal monitoring.

References1. Rodien P, Jordan N, Lefèvre A, et al. Abnormal stimulation of the thyrotrophin receptor during

gestation. Hum Reprod Update 2004;10:95-105. 2. http://www.thyroidmanager.org/chapter/thyroid-regulation-and-dysfunction-in-the-pregnant-patient/ 3. Barbesino G, Tomer Y. Clinical review: Clinical utility of TSH receptor antibodies. J Clin Endocrinol

Metab 2013;98:2247-55.



Mildly elevated free T4Suppressed TSHNot consistent with 3rd trimester thyroid

function testsConsistent with hyperthyroidismSuggestive of hyperthyroidism?Early hyperthyroidism ?Subclinical hyperthyroidism in pregnancy

Gestational transient hyperthyroidism unlikely

hCG consistent with gestational ageTSH suppressed in pregnancy?Graves' disease?On T4 replacementSuggest TRAb / TSI testingSuggest anti TPO/Tg antibodiesSuggest review by specialistRepeat thyroid function tests postpartumUse reference range for pregnancySuggest thyroid function tests in newborn

?Clinical review/Patient historyIncreased risk pre-eclampsia, intra-

uterine growth retardationMonitor thyroid function testsRepeat thyroid function testsNormal free T3?ThyroiditisRisk of neonatal thyrotoxicosis in Graves'Increased risk hydrops, preterm deliverySuggest urine creatine/proteinSuggest serum uric acid, liver function

tests?Autonomous thyroid noduleSuggest full blood examination/ESRThyroid uptake scan contraindicated in

pregnancy?Anti-thyroid drugInterpret pregnant TSH with cautionSuggest FSH/LH/prolactinSuggest ultrasound scanNot trophoblastic diseaseMeasure total T4Phone resultsSubclinical hyperthyroidism no adversity

to pregnancyGraves' can worsen post-partumHigh hCG can cause hyperthyroidism 1st

trimesterIncreased risk obstetric complications?Iodine-induced hyperthyroidism

?Transient gestational hyperthyroidism?Sick euthyroid?Assay interferencehCG not consistent with gestational age?Due to elevated hCGEuthyroid results?Trophoblastic disease?HypopituitarismRepeat free T4/free T3 by different assayRepeat hCG?Corticosteroid excessTotal T4 of greater value than free T4Check erythrocyte zincNot indicative of thyroid disease?Germ cell tumourSuggest thyroid uptake scan?Transient gestational hyperthyroidismSuggest TBGSuggest full pre-eclampsia screen

http://www.thyroidmanager.org/chapter/thyroid-regulation-and-dysfunction-in-the-pregnant-patient/

Case 12-03 Thyroid



Clinical Notes on Request FormPast history of papillary thyroid cancer

Case DetailsTSH 0.89 mIU/L (0.5–4.0)Free T4 15 pmol/L (10–25)

Additional InformationPrevious total thyroidectomy.On thyroxine.

Suggested CommentIn a patient with a history of thyroid cancer, aim to suppress thyroid-stimulating hormone (TSH) below 0.1 mIU/L to minimise the risk of recurrence. If the patient has been disease free for at least 5 years, American Thyroid Association guidelines suggest maintaining TSH between 0.1 and 0.5 mIU/L may be appropriate.

RationaleMost papillary thyroid cancers express the thyroid-stimulating hormone (TSH) receptor; high dose thyroxine TSH suppression therapy reduces tumour cell growth and survival. Meta-analysis of initial management of all, except stage I papillary thyroid cancer supports suppression of serum TSH below 0.1 mIU/L. This concentration was probably chosen because of inclusion of historical data using earlier generation TSH assays; some studies support complete TSH suppression. For low risk patients, initial suppression of serum TSH at or slightly below normal (0.1–0.5 mIU/L) is considered appropriate.

Longer-term management has lower quality evidence with regards to the degree of TSH suppression recommended. In persistent disease, the consensus is to maintain suppression below 0.1 mIU/L indefinitely. In patients who have high-risk disease and are disease free, TSH suppressive therapy should be maintained to achieve serum TSH concentration of 0.1–0.5 mIU/L for 5–10 years. In patients who are at low risk and are disease free, the consensus is that TSH may be allowed to rise to between 0.3 and 2.0 mIU/L (evidence level C).

The risk profile of a patient depends on completeness of tumour resection, presence of tumour invasion/ metastasis, histological features of tumour and presence of 131I uptake outside of thyroid bed after thyroid remnant ablation. Of note, biochemical surveillance of recurrent disease should include concurrent measurement of thyroglobulin and anti-thyroglobulin (TgAb) antibodies. An elevated TgAb may interfere with thyroglobulin measurement, rendering the result unreliable. When present, the titre of TgAb may be used as a surrogate tumour marker.

Reference1. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated

Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214.



TSH <0.1 mIU/L for high risk diseaseInadequate suppression of TSHTSH suppression recommendedRefer to American Thyroid Association Guidelines

TSH 0.1–0.5 if high risk disease freeLow-normal TSH OK if 5–10 yrs disease free

Achieve TSH <0.1 mIU/LTSH <0.1 mIU/L for persistent diseaseTSH 0.3–2.0 if disease free and low risk Suggest monitorSuggest thyroglobulin? Likelihood of recurrenceSuggest thyroglobulin antibodies

Clinical history notedEuthyroidReview thyroxine doseNormal reference range does not apply?Patient complianceIncrease thyroxine dose?Extent of the diseaseTSH 0.1–2.0 mIU/L for low risk diseaseTSH 0.1–0.5 mIU/L for low risk?Residual thyroid diseaseIdeal TSH <0.01 mIU/L?Treatment by specialistIdeal TSH 0.1–0.5 mIU/LTailor thyroxine therapyReview patient's current clinical detailTSH total suppression for high risk

disease Maintain TSH between 0.1–0.01 mIU/LTSH should be <0.03 mIU/L

Adequate thyroxine replacementRefer to EndocrinologistSuggest 131-I scan if indicatedSuggest calcium and PTHSuggest TSH stimulation thyroglobulinTSH 0.05–0.1 mIU/L for low riskTSH <0.01 mIU/L for high riskTSH <0.1 mIU/L for low risk diseaseRisk of hyperparathyroidismFT4 level only if ?complianceSuggest lipidsLow thyroglobulin negative predictor

MISLEADING KEY WORDSInadequate medical historyNo commentSuggest free T3 Average TSH inversely associated with

relapse

Case 13-07 Thyroid


Patient Location General Practice Clinic

Clinical Notes on Request FormPre-conception testing. Nil Medication.

Case DetailsTSH 4.5 mU/L (0.5–4.0)Free T4 14 pmol/L (10–25)TPO Antibodies 42 kIU/L (<30)

Suggested CommentConfirm subclinical hypothyroidism by repeat testing. If confirmed, consider thyroxine replacement. Poor pregnancy outcomes have been described in women with raised TSH.

Rationale Thyroid dysfunction during pregnancy can result in serious complications for both mother and foetus. Current US Endocrine Society Guidelines recommend prenatal measurement of TSH for individuals considered high risk for thyroid disease. They include women with personal/family history of thyroid disorders, autoimmune disorders (including type 1 diabetes mellitus), goitre, symptoms or signs of hypothyroidism, positive thyroid antibodies, > 30 years old, infertility or history of miscarriage and preterm labour.

Individuals with TSH >2.5 mIU/L confirmed by repeat testing prior to conception, should be treated with low-dose thyroxine therapy with an aim to reduce TSH to <2.5 mIU/L. Subclinical hypothyroidism should be treated irrespective of whether the TPO antibody is positive or negative. The aim of treatment is to maintain TSH <2.5 mIU/L in the 1st trimester and <3.0 mIU/L in the 2nd and 3rd trimester, or within method- and trimester-specific TSH reference intervals, where available. Repeat testing should be performed at 6–12 weeks and 6 months postpartum as there is a higher incidence of postpartum thyroiditis in antibody positive women. Therapy can be discontinued if pregnancy is not achieved or postpartum. In the absence of an elevated TSH, a woman with known elevations of TPO antibodies should be screened for thyroid abnormalities before pregnancy and during the first and second trimesters.

Reference1. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy

and post partum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-65.



Subclinical hypothyroidismSlightly raised TSHMaintain TSH in trimester specific reference range

Increased risk pregnancy/foetal complications

?Risk of overt hypothyroidism?Subclinical hypothyroidism?Early/borderline hypothyroidismDelay pregnancy until diagnosisIncreased risk of postpartum thyroiditisAutoimmune thyroid diseaseSuggest replacement T4Suggest T4 replacement - aim TSH<2.5Suggest referral to endocrinologistSuggest repeat thyroid function testsSuggest treatment/counsellingCall GP to discuss

Low positive TPO Ab titreSuggest monitor thyroid function testsNormal FT4Consider Hashimoto's thyroiditisIncreased TSHExclude non-thyroidal diseaseRepeat thyroid function test in 1–3

monthsSuggest lipid studiesRepeat thyroid function test in 6 weeksConsider patient/family history?Iodine deficiency?Evolving autoimmune thyroiditis?Associated with infertilitySuggest check for goitreExclude TSH heterophile antibodyExclude non-toxic goitreSuggest physical examinationSuggest TSH receptor AbsSuggest cortisol levelsRepeat thyroid function tests at early 1st

trimester?Primary hypothyroidism

Suggest antithyroglobulin AbsSuggest monitor TPO Ab levelsSuggest thyroid ultrasoundSuggest ANA/dsDNA/AMASuggest rheumatoid factorExclude multinodular goitre Exclude thyroid carcinomaExclude hypogonadismExclude hypoparathyroidismSuggest 21-hydroxylase AbSuggest transglutaminase IgA AbSuggest anti-gliadin AbExclude idiopathic myxoedemaSuggest iodine supplementationExclude drug interferencesSuggest glucose/HbA1c testsSuggest ECGSuggest CK levelSuggest full blood examination

MISLEADING KEY WORDSExclude Grave's DiseaseSuggest test for FT3Euthyroid resultsRepeat thyroid function tests in 6 months

Case 10-06 Pituitary



Clinical Notes on Request FormAmenorrhoea, nausea and vomiting.

Case DetailsProlactin 3145mU/L (<500)

Additional InformationPrevious results (a few days ago in Emergency Department)

Prolactin 195 mU/LAll reproductive hormones were within reference intervals and hCG negative.

Suggested CommentAssuming both samples were measured by the same method and laboratory errors have been excluded, the most likely cause of a rapid increase in prolactin concentration with the given the history would be medications that block the dopamine receptors e.g. antiemetics, antipsychotics, antidepressant and antihypertensive. Recommend repeating prolactin after discontinuation of interfering medication. If hyperprolactinaemia persists, further investigations are warranted.

Rationale There are many causes of a raised prolactin including pregnancy, nipple stimulation, stress, prolactinomas, hypothalamic and pituitary disorders, oestrogens, drugs, hypothyroidism, chest wall injury, and chronic renal failure. Hyperprolactinaemia may also be due to idiopathic causes and macroprolactinaemia.

In this case, there has been a rapid rise in the prolactin concentration over a few days and it is not possible to know which result is correct. It is important to exclude any error in the total testing process, such as stress of phlebotomy, sample mix-up or the use of a different analytical method that may be affected by macroprolactin or hook effect.

This patient has amenorrhoea, which may be due to the elevated prolactin. She also has nausea and vomiting that could have been treated with an antiemetic drug. Prolactin concentrations of >3,000 mU/L are usually due to pregnancy, drugs, prolactinomas, hypothalamic and pituitary disorders. In this case pregnancy has been ruled out, and prolactinomas, hypothalamic and pituitary disorders usually develop over a longer period of time and are unlikely to present in such an acute manner. Therefore, the most likely cause of the hyperprolactinaemia would be medications e.g. antiemetics. The prolactin should be remeasured after stopping any interfering medications for four days. The amenorrhoea is possibly due to another cause and may warrant further investigations.

References1. David SR, Taylor CC, Kinon BJ, et al. The effects of olanzapine, risperidone, and haloperidol on

plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085-96. 2. Dostál C, Marek J, Moszkorzová L, et al. Effects of stress on serum prolactin levels in patients with

systemic lupus erythematosus. Ann N Y Acad Sci 2002;966:247-51.



Marked hyperprolactinaemiaPrevious normal prolactin levelAcute rise in serum prolactinDiscrepancy between two prolactin

resultsRepeat prolactin - no drugs, no stressPituitary disease unlikelyPituitary disease unlikely, consider drugs

Macroprolactin unlikelyRecent negative hCG notedPregnancy unlikely?Drug interaction?Tricyclics, antihypertensives,

psychotropic?Antiemetic medication?Antipsychotic medication?Dopamine antagonist drugs?Acute stress e.g. illness?Different prolactin methods and units?Previous result high dose hook effectSuggest medication reviewSuggest repeat prolactinSuggest clinical reviewRetest both samples in dilution

?Pituitary tumour/prolactinomaHyperprolactinaemiaSuggest screen for macroprolactin?Stress, anxiety, exerciseSuggest thyroid function tests?HypothyroidismSuggest pituitary MRISuggest repeat hCG?Wrong specimenSuggest FSH, LH, oestradiol,

progesterone, 17OH progesterone?Galactorrhoea/lactationSuggest pituitary function testsSuggest cortisol?Epileptic seizureSuggest renal function tests and liver

function testsRerun with PEG precipitation or different

method?Hypothalamic dysfunctionNote nausea and vomitingExclude heterophile antibodiesSecretion pulses and various stimuliAmenorrhoea consistent with

hyperprolactinaemia?Subarachnoid haemorrhageRe-run both samples to confirm prolactin?Chest wall damageReserpine may cause nausea and

vomitingIdiopathic hypersecretion of prolactin

?Non-pituitary disease e.g. renal failure, cirrhosis, polycystic ovaries

Exclude pregnancy?PregnancySuggest BMI for anorexia nervosa?Breast manipulationSuggest TRH stimulation test

Case 9-05 Adrenal



Clinical Notes on Request FormPrevious microadenoma

Case DetailsDexamethasone Suppression Test

Day Time (h) Cortisol (nmol/L) Reference Interval1 0900 319 (160–650)1 2300 1.0 mg oral dexamethasone given2 0900 286 (<50)

Additional InformationDay 1 0900 AMACTH 21 ng/mL (9–51)

Suggested CommentThere was inadequate cortisol suppression following dexamethasone suppression test. Failure to suppress is consistent with Cushing’s syndrome. However, other causes of non-suppression include exogenous oestrogens, alcoholism, depression, non-compliance or malabsorption of dexamethasone and due to certain drugs e.g. phenytoin. Given the past history and an ACTH within the reference interval this is suggestive of pituitary-dependent Cushing’s syndrome.

Rationale Cushing’s syndrome is an uncommon disease of cortisol excess, which may be endogenous or exogenous in origin. The clinical diagnosis is often not straightforward and requires additional tests. The initial screening tests include urine free cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hour dexamethasone suppression test. The former two tests require at least two separate measurements. The 1 mg overnight dexamethasone suppression test (given between 2300 and 0000 h, with serum cortisol measured next morning at 0800 h), at a cut-off of 50 nmol/L, has a sensitivity >95% and a specificity of 80%.

False positive results occur with variable absorption and metabolism of dexamethasone. Drugs that induce the hepatic enzymatic clearance through the CYP3A4 pathway, such as phenytoin and alcohol, can have this effect. Up to 50% of women taking the oral contraceptive pill fail to suppress due to increased levels of cortisol binding protein. If an initial test returns positive, the finding should be confirmed with an alternate test. The diagnosis of Cushing’s syndrome is established by concordantly positive results from two different tests. The underlying cause of the hypercortisolism should be investigated accordingly. Patients with suspected Cushing’s syndrome should be referred to an endocrinologist for further evaluation.

Reference1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society

Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-40.



Inadequate suppression of cortisolSuggests Cushing’s syndrome?Stress, illness, infection, alcohol?Drug therapy e.g. phenytoin?Dexamethasone non-compliance/

malabsorption?Depression?Cushing’s disease?Oestrogen therapy?Enhanced dexamethasone metabolism?Pseudo-Cushing’s syndromeSuggest extended DSTSuggest high dose DSTRefer to EndocrinologistRecommend follow up Adrenal cause unlikely

?Obesity, eating disorder, weight lossNormal baseline ACTHSuggest recurrence of functional

microadenoma?Ectopic ACTH productionSuggest ACTH-dependent Cushing’s

diseaseNormal baseline cortisolFalse positive possibleACTH not suppressedChange in hypothalamic/pituitary/adrenal

axisReview clinical presentationSuggest pituitary and thyroid function

testsSuggest MRISuggest late evening cortisol levelMeasure ACTH with dexamethasone

suppression test?DiabetesSuggest CRH stimulation test?Adrenal tumour?Exogenous steroid?Pituitary diseaseSuggest salivary free cortisol?Hyperthyroidism/acromegaly Suggest 24 hour urine free cortisolSuggest 2 mg dexamethasone suppression test

Suggest serum potassiumAdrenocortical hyperfunction

Suggest low dose dexamethasone suppression test

Suggest day 2 dexamethasone levelHypercortisolismSuggest petrosal sinus ACTH and cortisol

Result inconclusiveNormal responseExcludes Cushing’s syndrome?Metabolic syndrome?Cyclic Cushing’s syndromePituitary disease unlikelySuggest insulin hypoglycaemia testExclude pituitary-independent Cushing’s

Case 11-05 Adrenal


Patient Location Medical Outpatients (Diabetes Unit)

Clinical Notes on Request FormType 2 diabetes; to exclude Cushing's syndrome

Case DetailsDexamethasone Suppression of Cortisol

Day Time (h) Cortisol (nmol/L) Reference Interval1 0900 414 (160–650)1 2300 1.0 mg oral dexamethasone given2 0900 329 (<50)

Additional InformationTwo weeks earlier:Dexamethasone Suppression of Cortisol

Day Time (h) Cortisol (nmol/L) Reference Interval1 0900 358 (160-650)1 2300 1.0 mg oral dexamethasone given2 0900 <35 (<50)

Suggested CommentCortisol is not suppressed after 1 mg dexamethasone in contrast to the results two weeks earlier. This could be due to a lack of compliance in the current test or specimen mix-up in either the previous or this test. Serum dexamethasone measurement could clarify compliance and specimen identity. Rare possibility of cyclical Cushing’s could be considered. Recommend assessment of midnight salivary cortisol or 24 hour urine free cortisol.

Rationale Poorly controlled diabetes mellitus can be associated with mild hypercortisolism and abnormal dexamethasone suppression tests. However, a clearly suppressed test a fortnight previously with a clearly unsuppressed result now should prompt consideration of non-compliance with dexamethasone in the second test or sample mix-up in either the first or the second test. Measurement of serum dexamethasone concentration may clarify these, but the test is expensive and not commonly available.

Increased metabolism of dexamethasone by ethanol abuse or glitazone therapy initiated in the interim is unlikely in view of the short interval. Other causes of false positive dexamethasone suppression test such as obesity, depression and oestrogen therapy are not considered for the same reason. Further testing with midnight salivary cortisol or with 24 hour urine free cortisol would be useful if pre-test probability of Cushing’s syndrome is high.

References1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society

Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-40.2. Yanovski JA, Cutler GB Jr, Chrousos GP, et al. Corticotropin-releasing hormone stimulation following

low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 1993;269:2232-8.

3. Vagnucci AH, Evans E. Cushing's disease with intermittent hypercortisolism. Am J Med 1986;80:83-8.



Inadequate suppression of cortisolDiscordant dexamethasone suppression test compared with previous

?Compliance with dexamethasone?Acute illness/stress?Cyclical Cushing’s syndrome?Test protocol followed?Mislabel of patient or sample?Malabsorption/rapid metabolism?Exogenous steroid/glucocorticoid?Alterations in medication?Transient Cushing’s syndrome Review clinical and medication historySuggest dexamethasone assaySuggest repeat dexamethasone suppression test

Suggest 24 hour urinary free cortisolSuggest midnight salivary cortisolSuggest 2x24 hour urinary free cortisolSuggest 2x late night salivary cortisolDifficult to interpret in diabeticsResults confirmed by repeat analysis

?Anticonvulsant therapy?Depression?AlcoholismDrug-induced rapid liver metabolism?Glitazone effectSuggest ACTH?Cushing's Syndrome?False positive?Obesity?Pseudo-Cushing’s?Exogenous oestrogenSuggest late evening cortisol?Poorly controlled diabetesSuggest 2 mg dexamethasone

suppression test?Reason for repeat?Change in patient’s conditionSuggest dexamethasone-CRH testSuggest HbA1c?Cause of discordant dexamethasone suppression test

Suggest pre/post dexamethasone 24 h urine cortisol

?Ectopic ACTH production?Renal statusResults inconclusive

Suggest high dose dexamethasone suppression test

Previous normal DST excludes Cushing’sSuggest imaging of pituitary and adrenal Suggest cortisol binding globulin

Case 7-05 Reproductive



Clinical Notes on Request FormNone

Case DetailsSerum hCG 14 IU/L (<5)

Additional InformationTwo weeks earlier:

hCG 21 IU/LClinical notes: LMP 15 weeks ago, inconclusive ultrasound

Two months earlier:hCG 121 IU/L

Clinical notes: ?pregnant

Suggested CommentPersistent low human β-chorionic gonadotrophin (hCG) suggests likely miscarriage with retained products of conception. Differential diagnosis includes low-grade gestational trophoblastic neoplasia or false positive hCG due to laboratory interference. Sample has been forwarded for analysis by another method. Suggest check urine pregnancy test.

Rationale Following the termination of normal pregnancy in the first trimester, the human β-chorionic gonadotrophin (hCG) concentrations fall in two trajectories. In the first two days, the half-life of hCG is approximately 0.63 days and increases to 4 days in the subsequent two weeks. By contrast, in termination of ectopic pregnancy, the hCG decreases by approximately 25% in the first two days. In trophoblastic neoplasia or persistent trophoblast following termination of pregnancy, the hCG concentrations may fall at even slower rate or rise.

Therefore, possibilities in this case are the following: failing ectopic pregnancy, incomplete miscarriage, failing second pregnancy, analytical problem (hook effect, heterophile antibody). The fact that the level is falling makes the presence of heterophile antibody less likely. The clinical note of normal menstrual period supports retained products of conception rather than an artefact. It may be prudent to check the hCG against another assay.

References1. van der Lugt B, Drogendijk AC. The disappearance of human chorionic gonadotropin from plasma and

urine following induced abortion. Acta Obstet Gynecol Scand 1985;64:547-52.2. Silva C, Sammel MD, Zhou L, et al. Human chorionic gonadotropin profile for women with ectopic

pregnancy. Obstet Gynecol 2006;107:605-10.3. Kadar N, Romero R. Further observations on serial human chorionic gonadotropin patterns in ectopic

pregnancies and spontaneous abortions. Fertil Steril 1988;50:367-70.



Slow decay in hCG level?Recent miscarriage?Retained products of conception?Ectopic pregnancy?Non-viable pregnancy?Incomplete miscarriage Suggest assay by different method

?False positive hCGSuggest repeat/monitor hCG?Molar pregnancyPersistent low hCGSuggest clinical reviewSuggest urine pregnancy testDecreasing hCG levelSuggest ultrasound or imagingSuggest further reviewSuggest heterophile Ab pretreatmentPatient not pregnantSuggest oestradiol and progesteronehCG may be present for 6 weekshCG half-life is 1-3 days?MalignancyEquivocal pregnancy result?Non-pregnancy source hCG?hCG assay type and reference rangeSuggest rheumatoid factorSuggest investigation for miscarriage

?New pregnancyLow levels for gestational ageSuggest beta/hyperglycosylated hCG assay

Suggest FSH, LHMalignancy unlikelyConsider D&CSuggest prolactinPrevious results noted Suggest group and Rh AbSuggest full blood count



Patient Location Endocrinology Outpatients

Clinical Notes on Request FormGynaecomastia

Case DetailsFSH 3 U/L (<10)LH 3 U/L (<9)Oestradiol 179 pmol/L (55–165)Testosterone 6.5nmol/L (11–40)SHBG 18 nmol/L (10–70)

Additional InformationAlpha Fetoprotein 4 µg/L (<12)hCG <2 IU/L (<2)Prolactin 426 mIU/L (<500)

Suggested CommentThe results indicate hypogonadotrophic hypogonadism, which is a known cause of gynaecomastia, although other clinical signs of hypogonadism would be expected. Drug causes, hyperthyroidism, renal failure and cirrhosis should be excluded. Oestrogen-secreting testicular or adrenal tumour cannot be excluded.

Rationale Gynaecomastia is the abnormal enlargement of breast tissue in males due to an absolute or relative (to androgen) excess of oestrogen concentration, or sensitivity. It is most commonly physiologic, being associated with puberty and aging, or idiopathic. Nonetheless, medically important causes must be excluded.

The most common identifiable causes are drug effects, which must be sought by history. Cirrhosis (particularly alcoholic cirrhosis), renal failure (with reduced testosterone and elevated gonadotropin values) and hyperthyroidism (due to increased aromatase activity and SHBG) may be accompanied by gynaecomastia. These causes are likely to have been identified by general pathology testing before the more specific tests are requested in the endocrine outpatient setting, as indicated in this case. It is however necessary to ensure that these factors are excluded.

Primary or secondary hypogonadism are important causes of gynaecomastia and the testosterone and LH results presented in this case are consistent with secondary hypogonadism. HCG-negative feminising tumours of the testes or adrenals are rare but may also cause this hormonal profile by feedback inhibition of gonadotrophins.

References1. Ismail AA, Barth JH. Endocrinology of gynaecomastia. Ann Clin Biochem 2001;38:596-607.2. Case Records of the Massachusetts General Hospital. Case 12-2000. A 60-year-old man with persistent

gynaecomastia after excision of a pituitary adenoma. N Engl J Med 2000;342:1196-204.



Abnormal oestradiol/testosterone ratio?Drugs/exogenous oestrogen? Hypopituitarism/hypothalamic?Hypogonadotrophic hypogonadism?Testicular neoplasm?Liver disease?Renal failure ?Secondary hypogonadism?HyperthyroidismSuggest urea and electrolytesSuggest testicular imagingSuggest thyroid function testsSuggest liver function testsSuggest pituitary tests/imaging

Low testosteroneIncreased oestradiolLH/FSH low/normal?ObesityConsistent with gynaecomastiaSuggest clinical review?Alcohol?Cancer (other/not specified)Suggest adrenal tests/imaging?Adrenal neoplasm?Genetic low testosteroneSuggest karyotypingNormal AFP, hCG and prolactinSuggest iron studiesIncreased conversion testosterone to

oestradiol?HaemochromatosisSuggest repeat testsOestrogen secreting tumourSuggest repeat am sampleNormal SHBGAndrogen deficiency syndromeLow calculated free testosteroneSuggest testicular tests

?Primary hypogonadismNo evidence testicular tumourNo evidence of tumour?Secondary to severe illnessNo commentRefer to Endocrinologist?HypothyroidismReduced SHBGMeasure free testosterone?Gender correction/reassignmentNormal free androgen index?Tissue androgen insensitiveNo evidence pituitary diseaseRefer to Chemical PathologistSuggest tumour markers




Clinical Notes on Request FormHirsutism, hoarse voice, increased libido for investigation. On L-thyroxine replacement.

Case DetailsTotal Testosterone 10.4nmol/L (<3.2)

Additional InformationFree T4 and TSH within reference interval.Prolactin 189 mIU/L (<500)

Suggested CommentAn androgen-secreting tumour must be excluded given the extremely high serum testosterone and signs of virilisation. Serum androgen profile including DHEA-S, and imaging would assist in distinguishing between adrenal and ovarian malignancy. Assess drug history as medication effect is possible but other causes of androgen excess (PCOS, CAH and Cushing's syndrome) are less likely at this testosterone concentration. Clinical endocrine review is recommended.

Rationale In terms of frequency, hirsutism is typically idiopathic or associated with polycystic ovarian syndrome (PCOS). The diagnosis of PCOS requires two of the following: 1) oligo/amenorrhoea, 2) clinical or biochemical evidence of hyperandrogenism, 3) polycystic ovaries on ultrasound. Less common causes are hyperprolactinaemia, drugs, congenital adrenal hyperplasia (CAH) and Cushing's syndrome. 17OH progesterone is a useful screening test for CAH while Cushing’s syndrome can be evaluated by using 24 h urinary free cortisol, dexamethasone suppression test or midnight salivary cortisol tests.

Androgen-secreting adrenal or ovarian tumours are rare causes of hirsutism, but should be suspected when the onset of virilisation is rapid, symptoms appear in the third decade of life or later, or when serum testosterone concentrations are markedly elevated. This has been variously defined as testosterone concentrations greater than 5.2–6.9 nmol/L or 2.5 times the upper reference limit for any assay. Although such tumours may cause more modest testosterone elevations (at concentrations usually seen in PCOS, CAH, etc), it is unusual for these non-malignant conditions to cause very high testosterone concentrations. DHEA-S, because of its almost exclusive production by the adrenal glands, is an important follow-up investigation. Concentrations greater than 13.6 μmol/L suggest an adrenal tumour.

Reference1. Barbieri RL, Ehrmann DA. Evaluation of premenopausal women with hirsutism. In: Basow DS, ed.

UpToDate. Waltham, MA, 2013.



Markedly raised testosteroneHyperandrogenismClinically virilising conditionUnlikely PCOS/Cushing’s given degree of elevation?Androgen-secreting tumour?Adrenal neoplasm/hyperplasia?Ovarian neoplasm?Exclude drugs/medicationsSuggest ovarian/adrenal imagingSuggest full androgen profileSuggest DHEAS/DHEASuggest androstenedioneDHEAS to test adrenal or ovary originRefer to endocrinologistFurther testing required

?PCOSSuggest FSH/LHSuggest testosterone/SHBG?21 hydroxylase deficiency (CAH)Suggest free testosterone / FAIRaised testosteroneSuggest 17OH progesterone?Cushing’s syndromeSuggest progesterone/oestradiolSuggest cortisolSuggest urine adrenal/androgen screenSuggest LH:FSH ratioSuggest 24h urine cortisolSuggest dexamethasone suppression testRepeat and confirm resultsRepeat testosterone by RIA or

LCMS/MS?Family historySuggest insulin resistance studyNormal thyroid function tests/prolactinSuggest ACTH?AcromegalyRepeat testosterone after extractionSuggest glucose?Ovarian hyperthecosisSuggest 17OH pregnenoloneSuggest 21 deoxycortisolSuggest GHSuggest midnight cortisol?Trophoblastic tumourSuggest IGF1DHEAS/oestradiol cross react with total

testosterone?11hydroxylase deficiencyIncreased androgens associated with

cardiovascular riskSuggest thyroid function tests and prolactin

Not hypothyroidism

Suggest adrenal/ovarian tumour markersSuggest CEA/CA125?Menopause?MEN II syndromeSuggest Synacthen stimulation testSuggest hCGExclude pregnancy




Clinical Notes on Request FormHirsutism. ?PCOS

Case DetailsFasting serum

Testosterone 3.4 nmol/L (0.2–2.6)SHBG >180 nmol/L (20–120)FAI 1.7 (<6)

Additional InformationOestradiol <75 pmol/LLH <1 U/LProgesterone <0.6 nmol/LFSH <1 U/L

Suggested CommentElevated SHBG and previously suppressed gonadotrophins are consistent with the use of the oral contraceptive pill (OCP). OCP use often invalidates biochemical assessment of androgen status. If OCP use is excluded, suggested further investigation includes thyroid function tests. Note that SHBG concentrations may not return to baseline for many months after cessation of the OCP.

Rationale The most common cause of this pattern of results, especially in women of this age, is treatment with the OCP. Exogenous oestrogens commonly are not detected by routine assays but are bioactive leading to low LH, FSH and oestradiol and elevated SHBG. Further interpretation depends on confirmation that the patient is on the pill or not. Note that in this case we are commenting on the testosterone, SHBG and free androgen index (FAI) results rather than the gonadotrophins and hormones and the comment should focus in this direction.

Given the clinical notes (?PCOS), it is likely that the requesting doctor is seeking biochemical evidence of hyperandrogenism to support a diagnosis of polycystic ovarian syndrome (PCOS). At this time, the normal FAI does not support or exclude the diagnosis of PCOS. The preferred approach would be to take the patient off the OCP and reassess the androgens. The benefits of confirming the diagnosis must be weighed against the effects of cessation of the pill. If the patient is not receiving the OCP, investigation for other causes of raised SHBG (and hypogonadotrophic hypogonadism) should be performed. This may include thyroid function tests (hyperthyroidism causes raised SHBG) and prolactin. Further investigation without confirmation of the patient’s medications is not warranted.



Increased SHBG contributing to increased testosterone

Mild elevation of testosterone?Exogenous hormone effect e.g. OCPOestrogens cause increase in SHBGReview patient’s meds/drug historyRepeat tests after cessation OCP

Elevated SHBGSuggest prolactinSuppressed FSH/LH Suggest thyroid function testsSuggest DHEAS/DHEASuggest 17OH progesteroneSuppressed oestradiol/progesterone?CAH/Late onset CAHSuggest cortisol?Hypogonadotrophic hypogonadismFAI is normal?PCOS?HyperprolactinaemiaIncreased testosterone?Hyperthyroidism?Increased adrenal/ovarian androgensSuggest androstenedione?Excessive weight loss/exercisePerform pelvic ultrasound?HypopituitarismHirsutism?Cushing syndrome?Tumour/lesionSuggestive of hyperandrogenism?Chronic liver diseaseRepeat testingSuggest glucose/insulin/IGF1Hypothalamic/pituitary disorderSuggest 24h urine cortisolConsistent with PCOS?Pituitary diseaseAdrenal/ovarian tumour unlikelyRotterdam criteria assist PCOS diagnosis?Exclude phenytoin/carb interference?Assay interferenceSuggest karyotype ?Turner’sClinical history requiredSuggest ACTHSuggest refer to

specialist/endocrinologistSuggest family historyInvestigate for porphyriaLH usually increased in PCOSNormal free testosterone?FAI should be <1.7?Mild androgen deficiencyIndicative anovulatory condition?Ovarian failureSuggest 3 alpha-AG?Haemochromatosis/iron studiesCheck iron studiesSuggest pituitary imagingSuggest dexamethasone suppression testAromatase inhibitorSHBG is elevated in hypogonadism

Not consistent with PCOS?Adrenal/ovarian cancer?Pregnancy/suggest hCGPCOS unlikely?Idiopathic hirsutism?Hypothyroidism




Clinical Notes on Request FormErectile dysfunction. ? cause.

Case DetailsTotal Testosterone 1.0 nmol/L (8.0–27.8)SHBG <2.0nmol/L (10–70)

Suggested CommentSevere hypogonadism and very low SHBG indicate exogenous androgen abuse is the more likely cause of the results. Consider assessing fasting lipids.

Rationale Sex hormone binding globulin (SHBG) is a protein that is regulated by sex hormones, thyroid and growth hormone. Oestrogen and thyroid hormone elevate SHBG while androgens and growth hormone suppress it. In hypogonadal males, SHBG concentrations are higher than in eugonadal men. Consequently, reduced concentrations of SHBG are unexpected in uncomplicated male hypogonadism and assessment of LH in this setting is unlikely to be helpful. Of note, pharmacologic androgens may not be detected by routine testosterone assays and may return suppressed results.

Reduced SHBG can also occur in obesity, hyperinsulinism, hyperprolactinaemia, severe hypothyroidism, acromegaly, nephrotic syndrome and exogenous androgen abuse. However, the extremely low SHBG concentration in this case and clinical presentation make androgen abuse a more likely cause of this combination of abnormal results. Hence, testing for other causes is not recommended until androgen abuse has been excluded. Other expected biochemical findings in men who abuse androgens include elevated triglycerides, increased LDL-cholesterol, reduced HDL-cholesterol and increased haematocrit (1).

Reference1. Dickerman RD, McConathy WJ, Zachariah NY. Testosterone, sex hormone-binding globulin,

lipoproteins, and vascular disease risk. J Cardiovasc Risk 1997;4:363-6.



Very low SHBG?Exogenous androgen useSuggest fasting lipids

Suggest LH, FSH, prolactinLow testosterone?Diabetes, obesity, metabolic syndromeSuggest thyroid function tests?HypothyroidismRepeat morning testosterone/SHBG?Supplements/medications/drugsSuggest glucose/glucose tolerance

test/HbA1c/BMISuggest ACTH, GH, IGF-1, cortisolSuggest liver function tests/urea and

electrolytes/Iron studiesLow testosterone due to low SHBGSuggest urine anabolic steroidsRefer to endocrinologistEvaluate hypothalamus-pituitary-gonadal

axisHypogonadismUnable to calculate free testosterone?Nephrotic syndromeSuggest 24h urine protein

?Primary or secondary hypogonadism?Congenital/genetic disease?Hyperprolactinaemia/ pituitary tumourSuggest free testosterone?Pituitary disease?Cushing’s syndrome?HyperinsulinismSuggest full blood examination?Orchitis/ haemochromatosis/ irradiation/ chemotherapy

?Malnutrition, exercise, stress?HypothalamicErectile problems due to hypogonadismConsistent with physiological not psychological

?Liver/renal disease, anaemia?Kallman’s syndrome, HIV, inflammation

?Developmental traumaSecondary hypogonadismSuggest semen analysis?Interferences; use different methodSuggest pituitary imagingSuggest test for haemochromatosis?Psychological problemsSuggest urine testosterone:epitestosteroneCalculated free testosterone highObesity, opiate, pituitary disease less likely


Consistent with androgen deficiency?Hyperandrogenism




Clinical Notes on Request FormAmenorrhoea

Case DetailshCG 9 IU/L (<2)

Additional InformationFSH 91 U/LOestradiol <37 pmol/L

Reference intervalFSH Oestradiol U/L pmol/L

Follicular 2–10 110–180Mid-cycle 7–24 550–1650Luteal 1–10 180–840

Suggested CommentIn post-menopausal women, hCG concentrations up to10 IU/L are not uncommon due to pituitary production. If a malignant source is suspected, suggest repeat testing after 2–3 weeks of high dose oestrogen to suppress pituitary hCG.

Rationale Low concentrations of hCG from pituitary production are common in peri- and post-menopausal women. The median concentration (range) in women <50 years and women ≥50 is 7 IU/L (2–19) and 10 IU/L (4–33), respectively (1). FSH levels have a strong negative predictive value for patients with hCG 5–14 IU/L to discriminate between placental (pregnancy, resolving abortion, gestational trophoblastic disease) and non-placental sources.

At FSH cut-off of <45 U/L, hCG of placental origin can be identified with 100% sensitivity and 75% specificity. On the other hand, FSH of >45 U/L is never observed in patients with elevated hCG of placental origin (2). Additional tests to determine the source of the hCG include: repeat testing; assay free beta hCG; heterophile antibody testing; and repeat testing after 2–3 weeks of high dose oestrogen oral contraceptive pill to suppress pituitary hCG (1).

References1. Cole LA, Laidler LL, Muller CY. USA hCG reference service, 10-year report. Clin Biochem 2010;

43:1013-22. 2. Gronowski AM, Fantz CR, Parvin CA, et al. Use of serum FSH to identify perimenopausal women

with pituitary hCG. Clin Chem 2008;54:652-6.



FSH and oestradiol consistent with peri/menopause

Low +hCG seen peri/post menopausehCG consistent with benign pituitary

productionElevated FSHMild elevation of hCGhCG level normal for menopause Low oestradiolConsistent with primary ovarian failureAmenorrhoea notedPregnancy not indicatedExclude heterophile antibodiesExclude 2° causes of +hCGExclude trophoblastic tumourExclude hCG of pituitary originExclude malignancyExclude germ cell tumourExclude non-trophoblastic tumourHormone replacement x 2 weeks / repeat

hCGSuggest serial hCGsSuggest OCP for 2–3 weeks / repeat hCGRepeat hCGRepeat hCG in 1–2 weeksPremenopause/non-pregnant reference

range

49 year old female?Specificity of hCG assayElevated LH expectedExclude liver disordersReference range of <2 notedSuggest TSH?HypothyroidismRequest further clinical historyExclude pregnancySuggest LH levels?History gestational trophoblastic diseaseElevated hCGMarkedly elevated FSHExclude gastrointestinal tract disorders

Repeat hCG at 48 h exclude pregnancyPremature ovarian failureRepeat FSH/oestradiolExclude dyslipidaemiaExclude familial persistent hCGSuggest prolactinExclude hormone therapySuggest progesterone levelsExclude autoimmune diseaseExclude diabeteshCG result not normalSuggest renal function tests


Suggest ultrasoundSuggest bone scanExclude osteoporosisSuggest abdominal CAT scan



Patient Location Endocrinology Outpatients

Clinical Notes on Request FormAmenorrhoea ?polycystic ovarian syndrome.

Case DetailsTotal Testosterone 5.1 nmol/L (0.5–2.6)DHEAS 4.2 µmol/L (4.0–10)SHBG >180 nmol/L (27–109)17-OH Progesterone 14.4 nmol/L (Follicular phase 0.5–3.3; Luteal phase 2.1–9.4)Prolactin 2119 mIU/L (59–619)

Suggested CommentThe combination of a markedly elevated sex hormone binding globulin (SHBG) with raised androgens and prolactin are consistent with pregnancy. Measurement of human chorionic gonadotropin (hCG) is advised.

Rationale Undiagnosed pregnancy (typically at the first or early second trimester) is always a differential diagnosis for amenorrhoea. Sustained increases in hCG, oestradiol and progesterone (including 17-OH progesterone) are early hormonal changes required for the viability of the embryo. During trimesters 1 and 2, sex hormone binding globulin (SHBG) production is stimulated by the increasing oestrogen levels, and consequently results in increased total (but not free) testosterone levels. At the same time, DHEAS levels decline due to increased metabolic clearance while prolactin increases in preparation for lactation. Another significant change (not included in this case) is a decline in TSH often to values well below those seen in non-pregnancy. The unique combination of all these findings is only seen in pregnancy and can be easily confirmed with measurement of human chorionic gonadotropin (hCG).

References1. Handbook of Clinical Laboratory Testing During Pregnancy. Ed: Gronowski AM. Totowa, NJ:

Humana Press, 2004.2. McClamrock HD. Androgen Production and metabolism in normal pregnancy. In: UpToDate, Barbieri

RL (Ed), UpToDate, Waltham, MA; 2013.



Results consistent with pregnancyRaised sex hormone binding globulin

(SHBG), testosterone, prolactin consistent with pregnancy

Exclude pregnancySuggest serum human chorionic

gonadotropin (hCG)

Suggest FSH, LH Exclude macroprolactinaemiaHyperprolactinaemiaExclude oral contraceptives?Congenital adrenal hyperplasiaResults do not suggest polycystic ovarian syndrome (PCOS)Elevated 17-OH progesteroneSuggest oestrogenRaised SHBG, testosterone, prolactinRaised SHBG - PCOS unlikelyExclude exogenous hormonal therapyRaised testosterone due to raised SHBGSpecialist management noted

Exclude PCOSExclude drug related/stressSuggest synacthen test with 17-OH progesterone

Suggest ovarian ultrasound?Pituitary adenomaSuggest morning cortisol?ProlactinomaExclude ovarian and adrenal tumoursExclude Cushing's SyndromeExclude pituitary diseaseSuggest IGF-1?Anorexia nervosaSuggest electrolytes and glucoseSuggest 17-OH progesteroneSuggest androstenedioneRepeat morning prolactinNormal DHEAS - adrenal tumour unlikely

Suggest liver function testsEuthyroidExclude renal impairmentSuggest insulin?CirrhosisSuggest urinary steroid profile?Causes of androgen excessSuggest CYP21A2 gene testingClinical correlation recommended.Suggest repeat tests after 3 months off oral contraceptive pills

Suggest dexamethasone suppression testExclude acromegalyRaised SHBG ?liver diseaseSuggest free testosteroneConfirm with raised blood pressure, ACTH and progesterone

Suggest progesterone and oestradiolNormal free androgen indexInvestigate virilisationExclude obesityNormal DHEAS excludes congenital adrenal hyperplasia

If PCOS - risk of gestational diabetesElevated prolactin not consistent with PCOS

?Dopamine suppressionWould not usually commentResults possibly consistent with oestradiol therapy

Suggest thyroid function testsSuggest 2h oral glucose tolerance test with HbA1c

Suggest fasting lipidsConsider idiopathic hirsutismConsider hypothalamus amenorrhoeaSuggest HbA1c

Suggest 11-deoxy cortisolSuggest 11-deoxy corticosterone


?Late onset congenital adrenal hyperplasia

Exclude hypothyroidismRaised testosterone and SHBG consistent with PCOS

Results consistent with late onset congenital adrenal hyperplasia

Hyperandrogenism with elevated free androgen index

Suggest growth hormoneNormal TSH excludes pituitary adenomaRaised prolactin and testosterone consistent with PCOS

Suggest 21-hydroxylase levelElevated testosterone suggestive of PCOS

Case 6-08 Iron



Clinical Notes on Request FormSevere anaemia

Case DetailsSerum Iron Studies

Iron 45 µmol/L (10–30)Transferrin 23 µmol/L (18–33)Transferrin Saturation 97% (13–47)Ferritin 2170 µg/L (20–300)

Additional InformationPrevious result 4 weeks ago:

Iron 13 µmol/L Transferrin 27 µmol/L Transferrin Saturation 23% Ferritin 122 µg/L

Recently transfused 2 units.

Suggested CommentThese results are incompatible with previous results and suggest iron overload. Markedly elevated ferritin could be caused by infection/inflammation or liver damage, but one would expect low iron and transferrin in the acute phase. Suggest liver function tests, C-reactive protein and repeat sample collection.

Rationale While frequent transfusion, as seen in patients with thalassaemia and after bone marrow transplantation, can cause iron overload and increase serum iron indices, a single transfusion does not elevate ferritin and only transiently elevates (<36 hours) iron and transferrin saturation (1, 2). Haemolysis after a transfusion reaction can release red cell ferritin, but a unit of packed red cells contains around 250 µg/L of ferritin and cannot explain the markedly changed result. The observed changes could be due to a sample mix-up or a combination of different factors elevating both the ferritin (inflammation, liver injury) and the iron (iron therapy).

References 1. Ho CH. The effects of blood transfusion on serum ferritin, folic acid, and cobalamin levels. Transfusion

1992;32:764-5.2. Saxena S, Shulman IA, Johnson C. Effect of blood transfusion on serum iron and transferrin saturation.

Arch Pathol Lab Med 1993;117:622-4.



Ferritin too high for transfusion only?Acute phase/infection /inflammation?IV/IM iron therapy?Liver disease?Sample mix-up Suggest liver function testsSuggest C-reactive protein/ESRSeek more clinical infoRecollect sample

Increased iron/saturation/ferritinIron overloadRepeat 4-12 weeksPrevious normal iron studiesSuggest full blood count/haemoglobin studies?HaemolysisIron studies unreliable due to transfusionIron deficiency unlikely?Haemochromatosis?Previous transfusionsNot iron overloadConsult pathologist

Secondary to transfusion?Transfusion reactionSuggest haemolysis markers/screen?Ineffective erythropoiesis?Chronic disease/malignancySuggest B12/folateSuggest HFE gene testingSuggest renal function tests/glucose/CA-125/otherHaemochromatosis excludedAnaemia of chronic disease?Aged/haemochromatosis blood productSuggest liver biopsy, CT scanCease iron therapy?Acute iron toxicitySuggest protein electrophoresisTreat with iron chelatorsNo commentFerritin too high for inflammation only

Case 7-01 Iron



Clinical Notes on Request FormInflammatory bowel disease. ?Iron deficient

Case DetailsIron 2 µmol/L (11–32)Transferrin 24 µmol/L (23–46)Transferrin Saturation 4% (13–48)Ferritin 57 µg/L (30–220)

Additional InformationHaemoglobin 100 g/L (115–155)Platelets 371 x109 (150–400 x109)Leucocytes 12.4 x109 (4.0–10.0 x109)Haematocrit 0.310 (0.36–0.49)MCV 85 fL (81–98)MCH 27.9 pg (29.0–33.0)MCHC 326 g/L (320–360)C-Reactive Protein 22 mg/L (<10)

Suggested CommentA low-normal transferrin and normal MCV suggests that anaemia due to chronic disease is more likely than iron deficiency. However, a normal ferritin level does not exclude iron depletion in the presence of inflammation.

Rationale Anaemia is the most common systematic complication of inflammatory bowel disease (IBD). In patients with mild/remitting disease, this should be screened for using haemoglobin, C-reactive protein and ferritin every 6-12 monthly. In active disease, the testing frequency should be at least 3 monthly.

Serum ferritin is a positive acute phase reacting protein and may be raised when inflammation is present. In IBD patients without clinical or biochemical evidence of inflammation, a serum ferritin of <30 µg/L would indicate iron deficiency. In the presence of inflammation, the lower limit of serum ferritin indicating normal iron stores is >100 µg/L.

Red cell indices may help in differentiating iron deficiency anaemia from anaemia of chronic disease, with a normal MCV favouring the latter diagnosis in this case. However, vitamin B12 and folic acid deficiency, if present, may complicate the picture, as they cause macrocytosis. The red cell distribution width may help in this scenario: a low value makes combined effects of vitamin and iron deficiency much less likely. Measurement of soluble transferrin receptor (with the calculation of TrR/log ferritin ratio) has been advocated in this situation although it is not widely accepted yet.

References1. Gasche C, Lomer MC, Cavill I, et al. Iron, anaemia, and inflammatory bowel diseases. Gut

2004;53:1190-7.2. Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron deficiency

and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545-53.



Transferrin borderline lowNormal MCVInflammationIron study affected by inflammation Ferritin is acute phase reactant?Anaemia of chronic disease?Effect chronic illnessIron deficiency not excludedSuggest soluble transferrin receptor

Iron deficiencyFerritin normalElevated C-reactive proteinIron lowTransferrin saturation lowAnaemia evident?InfectionElevated leucocyte countSuggest repeat at later dateSuggest trial iron therapyLow MCH/MCHCUnable to assess iron statusSuggest blood filmHaemoglobin lowReduced iron storesSuggest vitamin B12/folate?Blood loss?MalabsorptionFerritin lower than expectedIron deficiency unlikely?Nutritional stateConsistent with clinical notesSuggest occult blood and faecal cultureSuggest reticulocytes?Intestinal iron lossTransferrin normalSuggest bone marrow aspirationSuggest gliadin antibodies?Ineffective erythropoiesisLow haematocrit

Normal iron stores?Diurnal variation?Malignant diseaseSuggest liver function testsSuggest imaging?Haemoglobinopathy?Protein losing stateSuggest sigmoidoscopyErythrocyte parameters normalSuggest examination?Haemolysis

Case 8-10 Iron


Patient Location Medical Outpatient Department

Clinical Notes on Request FormIron deficiency?

Case DetailsIron 6 µmol/L (9–30)Transferrin 3.8 g/L (2.2–4.0)TIBC 86 µmol/L (50–90)Transferrin Saturation 7% (15–45)Ferritin 7 µg/L (20–150)

Additional InformationHb 104 g/L (110–180)MCV 69.8 fL (80–98)RDW 16.2% (<14.5)PLT 252 x109 (150–400 x109)WCC 8.6 x109 (4.0–15.0 x109)

Suggested CommentResults consistent with iron deficiency. Suggest further investigation for underlying causes such as blood loss, malabsorption or dietary deficiency.

Rationale In iron deficiency, serum ferritin, iron and transferrin saturation may be decreased while total iron binding capacity (TIBC), red cell protoporphyrin and soluble transferrin receptor (sTfR) may be increased. Of these, serum ferritin is the most powerful test. The diagnostic cut-off is 12–15 µg/L, but <50 µg/L with co-existent disease. sTfR/logl0 serum ferritin ratio provides superior discrimination in patients with chronic disease. Microcytosis and hypochromia are sensitive indicators of iron deficiency in the absence of co-existent B12 or folate deficiency, but are also present in haemoglobinopathies (e.g. thalassaemia), in sideroblastic anaemia and in some anaemias of chronic disease.

Gastrointestinal blood loss is the commonest cause in adult men and post–menopausal women (exclude colonic and gastric carcinoma by endoscopy). Malabsorption (exclude coeliac disease), poor dietary intake, blood donation, gastrectomy and use of non-steroidal anti-inflammatory (NSAID) medications are other common causes.

Reference1. British Society of Gastroenterology Guidelines for the Management of Iron Deficiency Anaemia.

http://www.bsg.org.uk/pdf_word_docs/iron_def.pdf

http://www.bsg.org.uk/pdf_word_docs/iron_def.pdf



Consistent with iron deficiencyIron deficiency Stage III (anaemia)Microcytic anaemiaThalassaemia unlikely?Blood loss?Gastrointestinal tract blood loss?Dietary/nutritional deficiency?Malabsorption?Coeliac diseaseSuggest gastroscopy/colonoscopySuggest coeliac antibodiesIron supplementation recommended

Low serum ferritinLow serum ironLow transferrin saturationSuggest occult bloodClinical assessment recommendedHigh normal transferrinIncreased total iron binding capacity?Thalassaernia traitMicrocyticIncreased red cell distribution widthInvestigate cause, post-menopausalMonitor iron studies/full blood countSuggest haemoglobin electrophoresisSuggest blood film reviewSuggest soluble transferrin receptor assayAnisocytosisSuggest MCH, red cell count?Intravascular haemolysisDepleted iron storesMonitor therapy with reticulocyte countIron deficiency Stage IISuggest follow up (not specified)?Abnormal vaginal bleeding

The facts speak for themselves?Pulmonary haemosiderosis

Case 11-04 Iron



Clinical Notes on Request Form?Abnormal LFTs. ?Cause

Case DetailsSerum Iron StudiesIron 60 μmol/L (10–27)Transferrin 2.73 g/L (1.50–3.00)Saturation 88% (20–50)Ferritin 1230 μg/L (30–400)Haemolysis +Icterus ++

Additional InformationT. Protein 68 g/L (60–82)Albumin 36 g/L (35–50)ALP 304 U/L (30–120)Bilirubin 134 μmol/L (<25)GGT 300 U/L (<50)AST 2407 U/L (<41)ALT 2019 U/L (<51)LD 505 U/L (50–280)

Suggested CommentThis patient has acute hepatocellular injury, which can cause markedly elevated ferritin levels. The increased serum iron concentration raises the possibility of haemochromatosis, although the latter does not usually present with acute hepatitis. Repeat iron studies after resolution of hepatitis are suggested and if persistently abnormal, genetic testing for haemochromatosis is indicated. The most common causes of acute hepatitis are viral hepatitis, alcohol, drugs, toxins, autoimmune hepatitis, and Wilson's disease.

RationaleIn acute hepatocellular injury there are marked increases in ferritin. As the liver ferritin is rich in iron, the percentage iron in transferrin stays the same. Iron is not commonly elevated in this setting (1). In acute phase reaction, not only are ferritin levels elevated but iron and transferrin are suppressed, which is not seen here. The typical changes seen in iron overload and genetic haemochromatosis are elevated iron and iron saturation, with concomitant high ferritin levels; however, transaminases are not markedly abnormal and only in advanced cirrhosis do the bilirubin levels increase. Therefore in this case the cause of the acute hepatitis needs to be investigated and explained before further attention is given to the iron studies.

Reference1. Brill S, Weinberg M, Graff E, et al. The status of serum iron and transferrin saturation in acute non-

hepatotrophic viral infections. J Med 2000;31:271-7.



Abnormal iron studies secondary to liver disease

Acute liver diseaseHepatocellular damageInterpret iron in context of liver diseaseAtypical of haemochromatosis alone?Alcohol/drugs/toxins?Hepatitis?Acute viral hepatitis?Wilson's disease?Metabolic/toxic/ischaemic injury?Autoimmune hepatitis?Acute alcohol hepatitis?Infectious mononucleosisSuggest repeat iron studies when liver

function tests normalise Suggest hepatitis serologySuggest EBV serologySuggest CMV serology

?HaemochromatosisSuggest HFE gene mutation analysis?Iron overloadHigh ferritinAbnormal liver function testsIncreased transferrin saturationElevated serum iron?HaemolysisMarked transaminitisSuggest full blood examinationAbnormal iron studiesSuggest clinical evaluation?Haematological disorder?Iron overdoseSuggest drug screen (including

paracetamol)Suggest autoantibodiesMixed hepatocellular/cholestasis?Inflammatory process?CholestasisSuggest repeat iron studiesSuggest clotting studies?Repeat blood transfusion?Chronic liver diseaseSuggest caeruloplasmin/copper?Porphyria cutanea tarda?Anaemia/B thalassaemia majorSuggest conjugated bilirubin?Acute phase response?InfectionRepeat iron studies on fasting specimen?Autoimmune diseaseSuggest blood alcoholSuggest testosterone/thyroid function

testsNormal transferrinSuggest imaging studies?Juvenile haemochromatosisSuggest repeat liver function tests?Herbal supplementsSuggest alpha-1-antitrypsin/phenotypeSuggest diabetes mellitus screeningSuggest porphyrin screen?Fatty liverSuggest renal function testsSuggest urine copperIron overload unlikelyHaemolysis not cause of abnormal iron

studiesHaemolysis can cause abnormal iron

studies

Iron overload resulting in liver disease?NeoplasiaSuggest liver biopsySuggest test/monitor AFPSuggest desferrioxamine challenge test?Vitamin B12/folate deficiency

Case 13-08 Iron



Clinical Notes on Request FormRheumatoid arthritis.

Case DetailsSerum Iron 5 μmol/L (10–27)Transferrin 3.0 g/L (1.5–3.0)% Saturation 7 % (15–45)Ferritin 48 μg/L (30–250)AST 31 U/L (5–55)

Additional InformationHb 140 g/L (130–180)MCV 85 fl (82–98)MCH 28 pg (27–52)

Suggested CommentIron studies suggest non-anaemic iron deficiency in the context of chronic inflammatory disease. Borderline low MCH also noted. Suggest consider oral iron replacement trial and repeat iron studies and full blood examination in 3 months with CRP. Consider gastrointestinal investigation for malabsorption (coeliac disease) or blood loss, if iron stores decline further or anaemia develops.

Rationale Ferritin is a positive acute phase reactant. In the setting of a chronic inflammatory condition such as rheumatoid arthritis, a ferritin of 48 μg/L does not guarantee normal iron stores. Rather, a level <50–60 μg/L together with the low iron saturation, borderline low MCH and borderline high transferrin all support iron deficiency; anaemia only occurs in the final stage of iron deficiency and is not (yet) present in this case. The prevalence of gastrointestinal malignancy is low in iron deficiency without anaemia and given the borderline results in this case, a conservative approach to further invasive investigation seems reasonable.

British guidelines suggest empirical oral iron replacement for 3 months and coeliac screen (by anti-tissue transglutaminase antibody testing) in this setting, although upper and lower gastrointestinal investigations could be considered in men >50 years depending on the clinical setting. Finally, patients with rheumatoid arthritis and iron-deficiency anaemia are likely to have more severe joint disease, but will respond to treatment if anaemia is corrected.

References1. Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency

anaemia. Gut 2011;60:1309-16.2. Pasricha SR, Flecknoe-Brown SC, Allen KJ, et al. Diagnosis and management of iron deficiency

anaemia: a clinical update. Med J Aust 2010;193:525-32.3. Wilson A, Yu HT, Goodnough LT, et al. Prevalence and outcomes of anemia in rheumatoid arthritis: a

systematic review of the literature. Am J Med 2004;116 Suppl 7A:50S-57S.



Borderline iron storesFerritin <100mg/LChronic inflammatory rheumatoid

diseaseFalse normal ferritin?Fe deficiencyAbsence of anaemiaIron deficiency not excludedTransferrin and ferritin acute phase

reactantsInflammation masks iron deficiencyInflammation can elevate ferritinPossible low iron stores?Iron deficiency due to

immunosuppressive drugs ?Chronic/acute inflammation

?Blood loss?Chronic disease?Iron deficiency with acute phase

reactionSuggest soluble transferrin receptorSuggestive of iron deficiencySuggest CRP/ESRMonitor full blood examinationSuggest creatinine/liver function testsSuggest ratio sTfR and log ferritinDiet and drug reviewMonitor 1–2 monthly

Low serum ironLow transferrin saturationNormal Hb and erythrocyte indicesNormal ferritinBorderline/high transferrinSuggestive of diurnal variation of serum

ironLow/normal ferritinSuggest rheumatoid factorSuggest vitamin B12/erythrocyte folateNormal transferrinMonitor ferritinSuggest repeat fasting early am iron

studiesLow/normal MCVCheck collection time Suggest hepcidin on GCMSSuggest reticulocyte-haemoglobin

equivalent and use Thomas plot

Anaemia of chronic diseasePossible iron deficiency anaemiaSuggest bone marrow aspirate/bone marrow iron stores

?Normocytic normochromic anaemiaComplicated by anaemiaSuggest erythropoietinSuggestive of normal iron studiesIron deficiency anaemia not indicatedMild disease/no progression or treatmentHigh ferritinAnaemia of chronic disease unlikelyAcute phase reaction unlikelySuggest gastrointestinal endoscopy

MISLEADING KEY WORDSSuggest faecal occult bloodIron deficiency unlikelySuggest iron sufficiencyNormal iron stores

Case 10-03 Tumour Markers


Patient Location Oncology Outpatients

Clinical Notes on Request FormMass in head of pancreas (of unknown aetiology) with stent placed 4 weeks ago for obstructive jaundice.

Case DetailsSerum CA 19-9 22 U/mL (<38)

Additional InformationPrevious result (4 weeks ago):Serum CA 19-9 5010 U/mL (<38)

Suggested CommentProvided specimen integrity and resection are excluded, the marked decrease in CA 19-9 is consistent with relief of biliary obstruction. The CA 19-9 concentration post-stenting does not differentiate a malignant from a non-malignant lesion and should be evaluated in the context of further clinical investigations.

Rationale CA 19-9 is the sialylated Lewis blood group antigen, and is absent in individuals with Lewis Le (a-b-) that make up 5% of Caucasian and 20–25% of African Americans. CA 19-9 concentrations greater than 1000 U/mL are observed in non-malignant conditions including obstructive jaundice, cholangitis, acute liver failure, acute hepatitis, alcoholic liver disease and acute pancreatitis. In patients with jaundice and elevated CA 19-9, it is recommended that CA 19-9 be repeated after relief of jaundice. The half-life of CA 19-9 has been variously estimated at between <1 day and 4-8 days. CA 19-9 is not recommended for the diagnosis of pancreatic cancer but is recommended for monitoring of treatment of patients with pancreatic cancer.

References1. Goonetilleke K, Siriwardena A. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical

marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33:266-70.2. Chintanaboina J, Badari AR, Gopavaram D, et al. Transient marked elevation of serum CA 19-9 levels

in a patient with acute cholangitis and biliary stent. South Med J 2008;101:661.3. Mauer KR, Lopatin RN, Hoffman WA, et al. Decrease in a markedly elevated CA19-9 level after

stenting of a benign pancreatic ductal stricture. Gastrointest Endosc 1995;42:261-3.



Marked decrease in CA 19-9CA 19-9 not a diagnostic tumour markerBenign/malignant not differentiatedCA 19-9 <38 U/mL tumour not excludedHalf-life is 4–8 days consistent with drop

Drop consistent with obstructed duct stenting

Non-cancer conditions can cause elevation

?High CA 19-9 due to obstructive jaundice

?Normal CA 19-9 due to lab error?Obstructive hepatobiliary diseaseSuggest further investigationsMonitor CA 19-9 in pancreatic cancer

CA 19-9 normal range post surgeryHigh CA 19-9 in pancreatic tumourRequest clinical informationSuggest biopsy of pancreatic massHigh CA 19-9 in pancreatitisSuggest repeat CA19-9Monitor CA 19-9Interpret CA 19-9 with caution?Antigen excess/hook effect?High levels due to inflammation?Hepatobiliary inflammationRaised CA 19-9 in gastrointestinal tract

tumours?Other causes of high CA 19-9?Chemo/radiotherapy/resectionReassay CA 19-9 22 U/mL in dilutionGood response to treatment?High CA 19-9 due to chronic liver

diseaseSuggest imagingMonitor liver function tests?Surgery to remove massReassay CA 19-9 22 U/mL sampleNo comment?High CA 19-9 due to cholangitisCA 19-9 increased in gastrointestinal tract

conditionsCA 19-9 levels related to tumour sizeSuggest liver function tests pre/post stentHigh CA 19-9 in ovary/ breast tumourHigh CA 19-9 in biliary cancer?Both CA 19-9 done on same platformCA 19-9 excreted in bilePancreatic mass causes jaundicePost surgeryExclude autoimmune pancreatitisAssume hook effect excludedNo evidence of resectionInput of oncologist not required

Pancreatic malignancy unlikely Suggest CEA to exclude malignancyClinical information not consistent with CA 19-9 drop

Likely malignancy?Heterophile antibodyPoor prognosis?Sclerosing cholangitis/

cholangiocarcinomaRemoval of tumour pancreas/ gastrointestinal tract

Case 11-09 Tumour Markers



Clinical Notes on Request FormScreening

Case DetailsPSA 2.2 µg/L (<2.51)

Additional InformationNo previous results

Suggested CommentA total PSA above the median for this age may be associated with a modest increased risk of prostatic neoplasia. Suggest repeat with free to total PSA ratio and mid-stream urine examination. PSA sample should be collected at least 48 hours after any prostate manipulation or ejaculation.

Rationale The Urological Society of Australia and New Zealand supports selected screening with PSA and digital rectal examination (DRE) in men after 40 years. It is assumed knowledge for the medical practitioner that the positive predictive value of PSA is increased when used in combination with DRE. This man’s PSA is above his age-related median, which is approximately 0.6–0.8 µg/L depending on method. It confers increased risk for prostate cancer. Assuming that the request in a man of this age was generated due to family history or significant personal concern, it seems reasonable to try and clarify the patient’s risk in a timely manner rather than waiting 12 months or more, even though his absolute risk of prostate cancer is small.

There are no guidelines on repeat testing interval. However, in Australia, the Medicare Benefits Schedule will rebate for one measurement of free to total PSA ratio in a calendar year for this case, where the total PSA is between the median and the upper limit of age-related reference interval to support early diagnosis. Urinary tract infections or prostate manipulation due to DRE, sexual intercourse, strenuous bike riding etc can elevate PSA. Free PSA is labile under normal laboratory storage and handling conditions. Retrospective testing for free PSA is unreliable unless performed within 24 hours of collection or the serum has been frozen at the time of sample preparation. A fresh, optimal sample is preferred for free to total PSA ratio estimation.

Reference1. Urological Society of Australia and New Zealand PSA Testing Policy 2009.



PSA above age-related medianProstatic carcinoma not excluded?Increased risk of prostatic neoplasia?Preanalytical variablesSuggest follow-up Suggest free/total PSA ratioSuggest clinical correlationSuggest digital rectal examSuggest repeat PSAExclude lower urinary tract infectionMonitor PSA using same assayConsider complexed PSAExclude acute causes

PSA within reference limitsPSA within age-related reference limitsReview family historySuggest repeat PSA in 12 monthsConsider PSA velocityNot an ideal screening testSuggest repeat PSA ratio in 12 monthsAssess other risk factorsPatient should be informed before testingPSA at upper end of reference rangeSuggest repeat PSA in 6 monthsScreening benefits not provenSuggest repeat PSA in 6–12 months?Reference rangePSA <10 µg/LSuggest repeat PSA in 2 yearsSuitable as a screening test?Medians for PSA

Suggest repeat screening in 2–4 yearsCheck PSA for hook effectLow PSASuggest repeat PSA in 5 yearsPSA testing not useful at this ageNo commentInform clinician of assay calibrationRecheck result with different assay

Case 7-10 Toxicology/TDM



Clinical Notes on Request FormAcute liver inflammation. ?cause

Case DetailsMini toxicology screen (serum):Paracetamol Not detectedSalicylate 116 mg/LEthanol Not detected

Additional InformationSodium 141 mmol/L (134–146)Potassium 3.9 mmol/L (3.4–5.3)Urea 1.8 mmol/L (3.0–8.0)Creatinine 65 µmol/L (60–110)Albumin 21 g/L (35–50)Total Protein 52 g/L (63–80)Bilirubin 408 µmol/L (<20)Alk. Phos. 155 U/L (35–105)ALT 3670 U/L (<41)

Suggested CommentUndetectable serum paracetamol does not exclude paracetamol-induced liver toxicity, if the sample was collected sufficiently long after exposure. Salicylate concentration is below the toxic range for recent acute exposure or ongoing chronic exposure. Note that hepatocellular damage is an uncommon outcome of salicylate exposure in adults. Viral studies as directed by history are suggested. Addition of serum AST is suggested.

Rationale A set of toxicology results has been produced for a patient with liver function tests consistent with acute on chronic liver disease with a note on the request form recognising the acute liver inflammation and querying the cause. Of the drugs measured on this request, paracetamol is the most important liver toxin and most frequent toxicologic cause of liver transplant. Importantly, a negative result doesn’t exclude paracetamol overdose as a cause of the acute liver damage at a time sufficiently long before the blood test for the paracetamol to have cleared from the circulation (half-life of paracetamol: 1–3 hours).

Salicylate overdose is a rare cause of acute hepatitis in adults, particularly when no other metabolic consequences of salicylate toxicity are noted. The undetectable serum alcohol makes this a less likely cause of the acute hepatitis. Note that for interpretation of all the drug concentrations, history taking and other evidence are important to determine the possible timing and extent of any overdose. Addition of AST may be of assistance as an elevated AST/ALT ratio would be consistent with hepatic necrosis due to a toxic insult. Note only those comments directly related to the results currently being reported are being scored as ‘preferred’ with exception of a suggestion for viral studies. Comments related to less common causes of hepatitis are marked ‘less relevant’ as they would most likely be second-line tests after common causes have been excluded. Many submitted comments were directed at interpreting the liver function tests and would not normally be attached to a set of toxicology results.



Paracetamol toxicity not excludedSalicylate below toxic levelsSalicylate unlikely causeEthanol toxicity not excluded?Time of ingestion?Drug history?Viral infectionSuggest hepatitis serologySuggest ALT/AST ratioBilirubin interferes with salicylate

analytically

Acute onsetHepatocellular damageHepatic inflammation/hepatitisLow albuminSalicylate toxicity not excludedHigh bilirubin?Toxic insultSuggest coagulation studiesHigh ALTSevere diseaseLow ureaSynthetic/conjugation impairmentUnderlying chronic diseaseSuggest AST/GGT/LDHHepatic failureParacetamol not detectedMixed obstructive hepaticSuggest acid-base investigations?Clinical historyMonitor salicylateALT mildly elevatedSuggest ammoniaSuggest liver imagingOngoing insult?Protein intake/lossSuggest drug screenSuggest liver autoantibodiesSuggest further investigationsNo evidence renal failureSuggest clinical examination?Wilson’s diseaseSuggest full blood examinationSuggest haemolysis markers?Adult Reye’s Syndrome?Acute biliary obstructionSuggest conjugated and unconjugated

bilirubin?Ischaemic insultSuggest alpha-l-antitrypsinALP due to cells swellingRepeat liver function tests?HaemolysisSuggest copper studiesSuggest iron studies?Alcohol abuserDiscuss with requesting doctor?Reduced drug clearance?Autoimmune hepatitis?Primary biliary cirrhosisMonitorRisk of liver failureSuggest monitor creatinineRisk of metabolic acidosis?Non-viral infectionSuggest glucose?Acute or chronic disease

Refer to pathologistSuggest immunoglobulinsVitamin K may be requiredSuggest AFPRepeat paracetamolChronic onset?Malignancy



Patient Location Nursing Home

Clinical Notes on Request Form?Temporal arteritis. Increased ESR. Diltiazem CR 240mg.

Case DetailsSerum carbamazepine level: <3 umol/L

Additional InformationList of medications: isosorbide, diltiazem, aspirin, hydrochlorothiazide, thyroxine, neo-cytamen, caltrate, ostelin, macu-vision, losec and prednisone.

Suggested CommentCarbamazepine was undetectable in the sample. Suggest check authenticity of request and compliance to medication.

Rationale Carbamazepine is not detected in the patient sample and is not amongst the many medications listed. One therefore questions whether the request is an authentic one. If so, one may question medication compliance, although this is usually expected to be well supervised in a nursing home environment. One might consider drug interaction with cytochrome P450 3A4 (CYP3A4)-inducing agents, leading to a reduced concentration, although none of the other drugs listed fall into this category. On the contrary, diltiazem is an inhibitor of CYP3A4 and might be expected to increase carbamazepine levels.



Carbamazepine not detectedCheck if patient is taking carbamazepineCarbamazepine not included in drug

historySubtherapeutic carbamazepine level?Correct test orderedCheck request correctCheck if carbamazepine prescribedResults suggest patient not taking

carbamazepineOther medications unlikely to cause low

carbamazepine?Correct dose carbamazepine given

Check collection time?Drug interaction (not specified)?Hepatic enzyme inductionReview patient’s medicationRepeat/monitor level?Preanalytical errorNo comment?Malabsorption?Patient withdrawn from diltiazemCheck electrolytes/renal functionTest because ?accidental ingestion

Diltiazem increases levels/decreases clearance carbamazepine

?Non-steady stateSuggest thyroid function testsSuggest liver function testsNote diltiazem levels unavailableUrgent review requiredMonitor patient?Due to interaction with diltiazemSuggest other testsSuggest increase carbamazepine doseRepeat test in steady-stateConsider peak levels?Patient fitting?InterferenceSuggest measure free carbamazepineConsider preanalytical factorsSuggest temporal artery biopsyReview thyroxine replacementCarbamazepine can alter thyroid function test results




Clinical Notes on Request FormParacetamol overdose 16 hours ago.

Case DetailsParacetamol 30 mg/L

Additional InformationALT 165 U/L (<40)

Suggested CommentSerum paracetamol concentration is potentially toxic and may warrant N-acetylcysteine (NAC) therapy since the blood concentration is above the toxic line on the treatment nomogram at 16 hours post ingestion. Moderately increased ALT suggests liver injury. Repeat ALT at end of NAC infusion together with INR, urea and electrolytes, blood gases and glucose.

Rationale The absorption of paracetamol in the small intestine is rapid, giving peak serum concentrations within 1-2 hours with pill formulations and sooner with liquid preparations (30 minutes). Ninety percent of absorbed paracetamol undergoes hepatic conjugation with sulphate and glucuronide, and are excreted in the urine. The remainder is metabolised into the highly reactive intermediary compound N-acetyl-p-benzoquinone imine (NAPQI) via the cytochrome P450 (mainly 2E1 and 3A4) pathways.

Normally, the NAPQI is immediately conjugated by intracellular glutathione and excreted in the urine. In the presence of excess paracetamol, and thence NAPQI, glutathione stores may become depleted, leaving NAPQI to bind with other proteins, causing hepatotoxicity. When this happens, N-acetylcysteine (NAC) is administered and works by serving as a glutathione replacement, a free radical scavenger, binding NAPQI directly and increasing microcirculatory oxygenation. Treatment with NAC within 8 hours can prevent all serious hepatic injury, but the efficacy decreases with increasing delay.

There are now well-defined guidelines for management of a single episode of acute paracetamol overdose. The treatment nomogram relates the paracetamol concentration and the known time elapsed since ingestion to determine potential toxicity and treatment recommendations. However, the treatment nomogram cannot be applied for repeated or staggered doses, or when time of ingestion is uncertain. ALT is used for assessment of liver damage and response to NAC therapy. Most patients develop AST/ALT elevations within 24 hours of ingestion and almost all will have elevations at 36 hours. Maximal hepatotoxicity occurs at 72–96 hours. A schedule for recommended investigations is detailed.

References1. Daly FF, Fountain JS, Murray L, et al. Guidelines for the management of paracetamol poisoning in

Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust 2008;188:296-301.

2. Algren DA. Review of N-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in paediatrics. Geneva: World Health Organization; 2008.



Toxic paracetamol level at 16 hoursNomogram paracetamol above treatment

lineElevated ALT consistent with

hepatotoxicityRisk of hepatotoxicityRefer to Med J Aust 2008 GuidelinesTreatment requiredTreat immediatelyN-acetylcysteine therapy recommendedMonitor treatmentRepeat ALT?Pre-existing liver dysfunction?Aetiology of increased ALTN-acetylcysteine effective up to 36 hour

Elevated ALT/transaminaseALT consistent with paracetamol

hepatotoxicitySuggest liver function testsSuggest repeat paracetamol levelRequest drug and alcohol historySuggest electrolytesAssess extent of hepatic damageConfirm dose information?Normal or slow release paracetamolSuggest AST/ALTSuggest platelet countSuggest biochemical reassessmentSuggest blood gasLiver damage usually >24 hour post

paracetamol overdoseN-acetylcysteine efficacy declines at 18

hourContact lab for further adviceClinical hepatitisPhone results?No clinical contraindications?Fasting stateSuggest anion gapSuggest full blood pictureConsult poisons informationPancreatitis reported in paracetamol

overdoseSuggest prothrombin time/international

normalised ratioSuggest urea and creatinineSuggest glucoseIs metabolic acidosis present?

Likelihood of paracetamol toxicity lowSuggest NH4, lactateBorderline paracetamol level No commentSuggest calculation of half life




Clinical Notes on Request FormPolyuria for investigation

Case DetailsSerum osmolality 315 mmol/kg (275–295)Urine osmolality 210 mmol/kg

Additional InformationSodium 140 mmol/L (134–146)Potassium 3.8 mmol/L (3.4–5.5)Bicarbonate 28 mmol/L (22–32)Urea 4.5 mmol/L (3.0–8.0)Creatinine 63 µmol/L (60–105)Glucose 4.3 mmol/L (fasting <5.5)Calcium 2.32 mmol/L (2.15–2.65)Albumin 43 g/L (38–50)Corrected calcium 2.30 mmol/L (2.15–2.65)

Suggested CommentConsider ethanol ingestion given the raised osmolar gap of 26 mmol/kg in the setting of history of polyuria. Ethanol can be measured, if required, in blood or detected in urine. Measurement of liver function tests may support regular ethanol use. A timed urine sample can be useful to separate urinary frequency from polyuria.

Rationale The raised osmolar gap [= measured osmolality – (2 × sodium + urea + glucose), normally ≤ 10 mmol/kg] suggests a substance found in significant concentrations such as ethanol, which can cause polyuria due to nephrogenic diabetes insipidus, rather than lithium etc, which are not found in concentrations to explain an osmolar gap of >20 mmol/kg. Urine osmolality suggests water diuresis rather than osmotic diuresis. Methanol, ethylene glycol etc, can cause a raised osmolar gap but in such concentrations would be expected to cause a significant acidosis and toxic effects. Metabolic acidosis is unlikely given the normal bicarbonate.

References1. Purssell RA, Pudek M, Brubacher J, et al. Derivation and validation of a formula to calculate the

contribution of ethanol to the osmolal gap. Ann Emerg Med 2001;38:653-9.2. Ogata M, Mendelson JH, Mello NK. Electrolyte and osmolality in alcoholics during experimentally

induced intoxication. Psychosom Med 1968;30:463-88.



Increased serum osmol gap ?Unmeasured osmoles No metabolic acidosis?Alcohol?Ethanol?Ethanol- induced polyuriaSuggest serum ethanol levelUrine osmolality consistent with water

diuresisSuggest 24 h/timed urine - check volumeSuggest check liver function testsDiabetes mellitus excluded?Medical history/medicationSuggest repeat serum osmolality

Inappropriately low urine osmolality?Diabetes insipidusElevated serum osmolality?Ethylene glycol?Methanol?Mannitol?Psychogenic polydipsiaSuggest urinary electrolytes?PolydipsiaExclude neurogenic diabetes insipidusExclude nephrogenic diabetes insipidusExclude diureticsSuggestive of diabetes insipidus?Hyperproteinaemia?HyperlipidaemiaDifferentiate central from nephrogenic

diabetes insipidusSuggest first morning urine osmolality?Isopropyl alcohol?Pituitary/head injurySuggest recollection of urine and serumEndocrinologist referral?SorbitolSuggest drug screen?Genetic nephrogenic diabetes insipidusNephrogenic diabetes insipidus not

indicated?Propylene glycolRenal deficiency not indicated?TetracyclinesConsider further investigationSuggest plasma chlorideExclude analytical errorSuggest carbohydrate-deficient transferrinExclude renal disease/concentration

defectSuggest urine creatinine levelExclude specimen contaminationSuggest urine microscopy, culture and

sensitivity

Suggest water deprivation testSuggest DDAVP in water deprivation test

Suggest lithium levelsSuggest ADH levels?KetoacidosisSuggest blood gas?Lactic acidosisSuggest head-spacer gas analysis?Fanconi syndromeSuggest phenytoin levelsSuggest MRI of brainSuggest lateral X-ray of skullSuggest chromosome analysisSuggest urine amino and organic acidsSuggest renin/aldosteroneSuggest TSH levels Contact duty biochemist?Evaporation artefactSuggest urine glucoseNormal serum chemistry

Case 14-05 Inborn Errors of Metabolism

Patient ID 9-day-old baby boy


Clinical Notes on Request FormTerm baby, 600 g weight loss and jaundice.

Case DetailsTotal bilirubin 442 µmol/LConjugated bilirubin 74 µmol/L (0–10)Unconjugated bilirubin 368 µmol/L

Additional InformationRandom glucose 1.9 mmol/L(Urine reducing substances +++)

Suggested CommentThe results are consistent with hyperbilirubinaemia due to galactosaemia. Recommend patient be placed on a lactose free diet until confirmation of galactosaemia by erythrocyte galactose-1-phosphate uridyltransferase (GALT) test. During this time other causes of hyperbilirubinaemia should be considered and assessed where appropriate.

Rationale This case is a typical presentation of classical galactosaemia in a newborn baby with hyperbilirubinaemia, hypoglycaemia and positive urine reducing substances. This combination should trigger the possibility of galactosaemia, even if the baby has had a normal newborn screening test (NBS). This is because the clinical features of galactosaemia may be delayed until breast-feeding has commenced. Furthermore, false negative NBS may be observed in patients who have a blood transfusion or soy-based formula prior to the NBS.

Classic galactosaemia is an autosomal recessive disorder of carbohydrate metabolism secondary to severe deficiency of the galactose-1-phosphate uridyltransferase (GALT) enzyme. Lactose should be eliminated from the diet immediately and samples should be collected for erythrocyte GALT and galactose-l-phosphate (Gal-1-P). In some centres, urinary galactitol is measured. Failure to cease lactose allows toxic metabolites to continue to accumulate resulting in rapid progression to liver failure, sepsis and death. Other causes of hyperbilirubinaemia should be excluded.

Note: not all Australian States (e.g. Victoria) offer galactosaemia testing as a part of NBS.

References 1. Gilmour SM. Prolonged neonatal jaundice: when to worry and what to do. Paediatr Child Health

2004;9:700‐4.2. Malone JI, Diaz‐Thomas A, Swan K. Problems with the newborn screen for galactosaemia. BMJ

Case Rep 2011; doi 10.1136/bcr.01.2011.3769.3. Berry GT. Galactosemia: when is it a newborn screening emergency? Mol Genet Metab

2012;106:7‐11.



Conjugated and unconjugated hyperbilirubinaemia

?Galactosaemia?Inborn error of metabolismSuggest red cell GALT activitySuggest lactose free dietSuggest galactose-1-phosphateSuggest galactitol

Hyperbilirubinaemia - investigateHypoglycaemiaReducing substance in urineSuggest liver function test/ thyroid

function tests/ renal function tests/ electrolytes

Suggest specialist referralWeight loss/failure to thriveUnconjugated hyperbilirubinaemiaCheck newborn screening resultsConjugated hyperbilirubinaemiaSuggest metabolic screenSuggest amino acidsSuggest liver ultrasoundLiver failure/dysfunction/obstructConjugated bilirubin >15% of total -

investigateAt risk of kernicterusSuggest C-reactive protein/ erythrocyte

sedimentation rateSuggest blood gasSuggest urine chromatography for

galactoseSuggest α-1 antitrypsinHospital admissionBreast fed/lactose formulaSuggest ketones?Fatty/organic acid disordersReview neonatal hypoglycaemiaSuggest urine non-glucose reducing

substances?GlycosuriaGive glucoseSuggest test parents for galactosaemiaAccumulation of galactose-1-phosphate/

galactoseIsoelectric focusing for Duarte variants?Deficiency of gluconeogenic enzymeRepeat LFT to monitor progressConjugated bilirubin >30 µmol/L

pathologicalSuggest lactateSuggest urine glucose

?Acute infection/sepsisSuggest full blood count including morphology

?Red cell destruction/haemolysis?HypothyroidismSuggest Coombs testSuggest septic screenPhototherapy/exchange transfusion?Neonatal hepatitisSuggest Rubella/Toxo/CMV/HCV/HepB?Glucose-6-phosphate dehydrogenase deficiency/phenylketonuria

Suggest ammonia?Hereditary fructose intoleranceSuggest blood group/antibody test?TyrosinaemiaSuggest clotting studies?Maternal diabetesSuggest urine microscopySuggest urine bile acidsSuggest insulin? α-1 antitrypsin deficiencySuggest cortisol/growth hormoneSuggest DNA testingABO/Rh incompatibility?Endocrine disorder?Lactose intoleranceDubin Johnson and Rotor syndrome?LipoidosisSuggest acylcarnitineCheck for delta bilirubin on Vitros?Renal tubular problemsSuggest haptoglobin/lactate dehydrogenase/plasma viscosity

?HypopituitarismSome POCT meters interference by galactose

?Trisomy 18,21/hereditary syndromes?Glycogen storage diseaseSuggest galactose-free diet


?Biliary atresiaExclude inadequate breastfeeding?Breast milk jaundice?Delayed bowel motilitySuggest haemoglobin electrophoresis/ stool exam

· web view?lithium - suggest levels?diabetic ketoacidosis/insulin physician consultation...

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